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Abstract

Amyloidosis is a group of diseases in which proteins become amyloid, an insoluble fibrillar aggregate, resulting in organ dysfunction. Amyloid deposition has been reported in various animal species. To diagnose and understand the pathogenesis of amyloidosis, it is important to identify the amyloid precursor protein involved in each disease. Although 42 amyloid precursor proteins have been reported in humans, little is known about amyloidosis in animals, except for a few well-described amyloid proteins, including amyloid A (AA), amyloid light chain (AL), amyloid β (Aβ), and islet amyloid polypeptide-derived amyloid. Recently, several types of novel amyloidosis have been identified in animals using immunohistochemistry and mass spectrometry–based proteomic analysis. Certain species are predisposed to specific types of amyloidosis, suggesting a genetic background for its pathogenesis. Age-related amyloidosis has also emerged due to the increased longevity of captive animals. In addition, experimental studies have shown that some amyloids may be transmissible. Accurate diagnosis and understanding of animal amyloidosis are necessary for appropriate therapeutic intervention and comparative pathological studies. This review provides an updated classification of animal amyloidosis, including associated protein misfolding disorders of the central nervous system, and the current understanding of their pathogenesis. Pathologic features are presented together with state-of-the-art diagnostic methods that can be applied for routine diagnosis and identification of novel amyloid proteins in animals.

Keywords

amyloid precursor protein amyloid signature protein Congo red immunohistochemistry mass spectrometry review

Amyloidosis is a group of diseases characterized by the deposition of insoluble, fibrillar protein aggregates, termed amyloid, in single or multiple organs, resulting in organ dysfunction.²⁴ Since amyloid is an insoluble fibrillar aggregate derived from native precursor proteins, amyloidosis is classified by its precursor protein.²⁴ According to the International Society of Amyloidosis, 42 amyloid precursor proteins have been reported in humans to date.²⁴

Systemic amyloidoses had been further classified into “primary amyloidosis” and “secondary (reactive) amyloidosis,” corresponding to amyloid light chain (AL) amyloidosis and amyloid A (AA) amyloidosis, respectively.^103,168,241 However, since AA amyloidosis is not always accompanied by a well-defined underlying inflammatory lesion and can be a primary disease,²²⁹ these two classifications should no longer be used. In recent years, it has been revealed that a wide variety of proteins may form amyloid, in addition to well-known amyloid precursor proteins such as serum amyloid A (SAA),^137,168 immunoglobulin light chain,^80,138,204 the amyloid β precursor protein (APP),^243,246 and islet amyloid polypeptide (IAPP).^109,184 Although AA amyloidosis is the most common type of systemic amyloidosis, recent studies have shown that other forms of amyloidosis, such as apolipoprotein A-IV (ApoA-IV) amyloidosis and fibrinogen Aα-chain amyloidosis, also present as systemic amyloidosis in animals.^97,224

Amyloid typing is necessary to determine the etiology and treatment strategy for each amyloidosis. For example, AA amyloidosis and AL amyloidosis are associated with chronic inflammation and plasmacytic proliferative disease, respectively.^5,166 In addition, some amyloidoses are associated with other neoplastic diseases^148,169,170 or aging.^84,97

This review provides an updated classification of animal amyloidoses (Table 1) and the current understanding of their pathogeneses. Pathological features are presented together with their etiology and available diagnostic methods for routine diagnosis and future identification of novel amyloid proteins.

Table 1.

Amyloid precursor proteins and their associated diseases/lesions in animals.

Precursor Protein	Systemic (S) or Localized (L)	Target Organs	Associated Diseases and Lesions	Tumor-Associated	Animal Species	References
Serum amyloid A	S	Liver, spleen, kidney	AA amyloidosis	No	Mammalian and avian species	^{9,60,121,142,155,166,175,177,195,223,262,278}
	L	Joint	Amyloid arthropathy	No	Chicken	¹³⁴
Immunoglobulin light chain	S	Kidney, liver, intestine	AL amyloidosis, multiple myeloma, bovine leukocyte adhesion deficiency	Yes	Horse, cow	^118,251
	L	Skin, intestine	Plasmacytoma	Yes	Dog, cat, horse	^{80,111,116,138,204}
Transthyretin	S	Heart, intestine, synovium	Transthyretin amyloidosis	No	Vervet monkey	^29,176
Apolipoprotein A-II	S	Kidney, intestine	Apolipoprotein A-II amyloidosis	No	Mouse	^86,85
Apolipoprotein A-IV	S	Spleen, kidney, intestine	Apolipoprotein A-IV amyloidosis	No	Cotton-top tamarin	²²⁴
Apolipoprotein C-III	S	Kidney (medulla), heart	Apolipoprotein C-III amyloidosis	No	Lion	¹²⁵
EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1)	S	Arterial walls, heart	EFEMP1 amyloidosis	No	Tsushima leopard cat	¹⁶¹
Fibrinogen Aα-chain	S	Kidney (glomeruli), heart, intestine	Fibrinogen Aα-chain amyloidosis	No	Japanese squirrel	⁹⁷
Apolipoprotein A-I	L	Lung	Apolipoprotein A-I amyloidosis	No	Dog	¹⁰⁸
Islet amyloid polypeptide (amylin)	L	Pancreas	Insulinoma, diabetes mellitus	Yes	Primates, felids, racoon, dog	^{16,109,185,280}
Insulin	L	Pancreas	Insulin amyloidosis	No	Common degu	⁸⁴
Calcitonin receptor-stimulating peptide 1	L	Thyroid	C-cell carcinoma	Yes	Cat	¹⁷⁰
Ameloblastin	L	Gingiva	Amyloid-producing ameloblastoma	Yes	Dog, cat	¹⁴⁸
Amyloid β precursor protein	L	Brain	Senile plaques, cerebral amyloid angiopathy	No	Mammalian and avian species	^189,246,282
Tau	L	Brain	Neurofibrillary tangles	No	Primates, felids, pinnipeds, bovids	^{3,31,32,53,226}
α-Synuclein	L	Brain	Pituitary pars intermedia dysfunction	No	Horse	⁵⁵
Prion protein	L	Brain	Transmissible spongiform encephalopathy	No	Bovids, deer, mink, felids, primates, camel	^190,227
α-S1-casein	L	Mammary gland	Mammary tumors	Yes	Dog	¹⁶⁹
α-S2-casein	L	Mammary gland	Corpora amylacea	No	Cow	¹⁸⁰
Lipopolysaccharide binding protein	L	Mammary gland	Needle-shaped amyloid deposition	Yes	Rat	¹⁷²
Keratin 5	L	Skin	Amyloid deposition around hair follicle	Yes	Dog	¹²⁴

Terminology

Amyloid

Amyloid is an insoluble fibrillar protein with a cross-β structure resulting from misfolding of native amyloid precursor protein.²⁴ The basic unit of an amyloid fibril is a protofilament, a stack of monomers forming a β-sheet, which twists with other stacks to form the fibril.²⁴ Amyloid fibrils are highly ordered and have stiffer properties than biological filaments such as actin.¹²³ Amyloid fibrils possess greater stability and resistance to degradation by chemical or biological means than the physiological state of the precursor proteins.⁸²

Amyloid was classically defined as extracellularly formed proteinous materials.²⁷⁴ Thereafter, aggregates of tau and α-synuclein were reported in association with various neurodegenerative diseases.^206,252 Since these aggregates are negative for Congo red staining (a gold standard method for amyloid identification, described below) and form intracellularly in neurons and glial cells, they have not been considered as amyloid but as “misfolded proteins” like prion.⁹⁴ However, these aggregates can also contain fibrils with a cross-β structure, share a common pathological nature with “classical amyloid,” characterized by cellular degeneration and proteostatic disorders, and can sometimes be found extracellularly. Therefore, the term amyloidosis in a broader sense, including such misfolding diseases, reflects current usage.²³⁰ In view of updated trends in nomenclature in the medical field,²⁴ this review also defines amyloid as a fibrillar protein with a cross-β structure. In other words, this review agrees to use the term amyloid not only for classical Congo red–positive pathological deposits but also for intracellular aggregates, functional amyloid, and in vitro synthetic fibrils, if they meet this definition. On the other hand, it is currently technically challenging to accurately characterize the nature of intracellular aggregates. For example, although tau and α-synuclein have demonstrated that some aggregates have amyloid properties, the pathology of tauopathy and synucleinopathy is not uniform, and it is not clear whether amyloid or nonamyloid aggregates are associated with the pathogenesis of these diseases.^66,91,154 With these understandings in mind, and although there are still ongoing debates, tau, α-synuclein, and prions are discussed as amyloid in this review.

Amyloidosis

Amyloidosis is a disease characterized by amyloid deposition in various tissues that results in functional abnormalities.²⁴ A small amount of amyloid deposits with no pathogenicity may be found incidentally on histologic examination without showing any related clinical signs. In such cases, it is appropriate to describe the histopathological findings (i.e., amyloid deposits) rather than diagnose amyloidosis (discussed below). In addition, although some neurodegenerative conditions present with amyloid formation, it may not be known whether amyloid or nonamyloid aggregates are involved in the pathogenesis. For these diseases, the term “protein misfolding disorder” seems to be more appropriate than “amyloidosis.”

Amyloid Signature Protein

Amyloid signature proteins are proteins that are not amyloid but colocalize with various amyloid proteins and are thought to be involved in amyloid deposition or inhibition.²⁴ Various amyloid signature proteins have been identified in humans and animals, including apolipoprotein E (ApoE), ApoA-IV, and clusterin.^24,159,160 The profiles of amyloid signature proteins differ among amyloid precursor proteins, affected tissues, and animal species (Table 2). The serum amyloid P-component (SAP) is an uncommon amyloid signature protein in animal amyloidosis, although it is frequently detected in human amyloidosis.^72,193 In fact, SAP colocalizes with primate amyloid^16,92,100 but is not detected in canine or feline amyloidosis.^59,160 Furthermore, SAP colocalizes with AA in adult pigs, but not in young pigs.⁹⁶ Previous studies of amyloidosis have focused mainly on amyloidogenic proteins, and the nature of amyloid signature proteins is still largely unknown. However, it is not difficult to imagine that these proteins, which colocalize or bind to amyloid fibrils, play an important role in the pathogenesis of amyloidosis.

Table 2.

Differences in amyloid signature proteins by amyloid precursor proteins and animal species.

Amyloid Precursor Protein	Amyloid Signature Proteins								References
Amyloid Precursor Protein	ApoA-I	ApoA-IV	ApoE	Clusterin	COL6A1	COL6A3	SAP	VTN	References
Serum amyloid A	Cat	Cat, island fox, red fox, pig	Cat, island fox, pig				Pig		^{59,96,160,211}
Immunoglobulin light chain	Dog	Dog	Dog						¹¹¹
Apolipoprotein A-II	Mouse		Mouse	Mouse				Mouse	¹⁵⁹
Apolipoprotein A-IV			Cotton-top tamarin	Cotton-top tamarin				Cotton-top tamarin	²²⁴
Apolipoprotein C-III	Lion	Lion	Lion					Lion	¹²⁵
EFEMP1	Tsushima leopard cat		Tsushima leopard cat	Tsushima leopard cat	Tsushima leopard cat	Tsushima leopard cat		Tsushima leopard cat	¹⁶¹
Fibrinogen Aα-chain			Japanese squirrel	Japanese squirrel				Japanese squirrel	⁹⁷
Amyloid β precursor protein							Chimpanzee		¹⁰⁰
Islet amyloid polypeptide		Cat	Cat				Rhesus macaque, sooty mangabey		^16,160
CRSP1	Cat	Cat	Cat	Cat	Cat	Cat			¹⁷⁰
Ameloblastin	Dog	Cat	Dog, cat	Dog				Dog, cat	^148,160
Keratin 5	Dog	Dog	Dog			Dog		Dog	¹²⁴
α-S1-casein	Dog	Dog	Dog	Dog				Dog	¹⁶⁹
Lipopolysaccharide-binding protein		Rat	Rat						¹⁷²

Abbreviations: ApoA-I, apolipoprotein A-I; ApoA-IV, apolipoprotein A-IV, ApoE, apolipoprotein E; Clus, clusterin; CRSP1, calcitonin receptor-stimulating peptide 1; COL6A1, collagen alpha-1(VI) chain; COL6A2, collagen alpha-2(VI) chain; COL6A3, collagen alpha-3(VI) chain; EFEMP1, EGF-containing fibulin-like extracellular matrix protein 1; SAP, serum amyloid P-component; VTN, vitronectin.

Amyloid Formation

Although the factors contributing to amyloid formation in vivo are diverse and complex, nucleation-dependent polymerization is considered the universal principle of amyloid formation (Fig. 1).^174,212 In the initial step of amyloidosis, a small number of precursor proteins are converted to intermediate species (specifically oligomers), which in turn can act as nuclei and facilitate further polymerization into protofibrils and fibrils by gathering precursor proteins. The initial small amyloid aggregate is often described as a “seed” because of its potential to grow into large aggregates and may even propagate to other organs in the body and form large aggregates or new seeds. Factors that initiate amyloidogenesis include (1) changes in stability or aggregability due to amino acid mutations or posttranslational modifications,^63,77,201 (2) destabilization of multimeric structures by mutations,¹⁴⁴ (3) increased self-interaction due to supersaturation of precursor proteins,^71,127,269 and (4) destabilization by proteolysis of full-length proteins.^169,212,236 In addition, other environmental factors, such as oxidative stress and free radicals, have been implicated in protein misfolding.¹ The speed of amyloid aggregation largely depends on the concentration of the amyloid precursor protein in the microenvironment surrounding seeds.²¹²

Figure 1.

Diagram of amyloid fibril formation. Many factors, such as mutations, proteolysis, and self-association of amyloid precursor proteins, may enhance misfolding and oligomerization. Oligomers can act as seeds that accelerate amyloid fibril formation in tissues. Elongated protofibrils twist together and form amyloid fibrils that are approximately 10 nm in diameter.

As described later, prions are transmissible among individuals, although they are not organisms with their own genome like virus or bacteria.⁴ Prion-like transmission and seeding properties have been experimentally demonstrated for other pathogenic amyloidogenic proteins such as SAA, apolipoprotein A-II (ApoA-II), tau, and α-synuclein.^{4,131,149,168} Some researchers have suggested collectively calling such amyloid-related diseases “prion disorders.”^8,26

Diagnostic Methods for Amyloidosis

Histologic Diagnosis

The identification of amyloidosis begins with the suspicion of amyloid deposits on hematoxylin and eosin–stained sections during routine diagnostic histologic evaluation, which can then be confirmed by additional special staining, particularly Congo red staining. Immunohistochemistry or mass spectrometry alone, described below, cannot confirm the diagnosis.²²⁴ Typically, amyloids in hematoxylin and eosin–stained sections can be observed as amorphous eosinophilic or pale basophilic material in the stroma and vascular walls.¹³⁰ For some types of amyloid, the precursor protein can be predicted based on their deposition patterns. The histologic characteristics of each amyloid are described below.

Congo red is commonly used for the histologic detection of amyloid.²⁷⁷ Although several methods for Congo red staining have been proposed, the authors recommend the alkaline Congo red staining method, which is currently widely used.²⁷⁷ Congo red–stained amyloid deposits show orange to red color in bright field (Fig. 2a, c), yellow to green birefringence under polarized light (Fig. 2b, d), and orange fluorescence under blue to green excitation light.²⁷⁷ The regular fitting of Congo red molecules into the molecular pockets on the surface of amyloid fibrils creates a crystal-like regularly ordered Congo red orientation, which may contribute to dichroic birefringence.²⁷⁷ Collagen and elastic fibers can also be stained with Congo red nonspecifically²⁷⁷ but can be distinguished from amyloid by their white birefringence under polarized light (Fig. 2b). Staining intensity may vary according to the severity of amyloid deposition, background tissue, animal species, and type of amyloid (Fig. 2). Notably, some amyloids, such as α-synuclein and tau, do not or poorly stain with Congo red.²¹⁸

Figure 2.

Congo red staining of AA amyloid in different animal species. (a, b) Kidney, cow. Glomerulus with mesangial amyloid deposits (a) shows yellow to green birefringence under polarized light (b). (c, d) Kidney, chicken. Amyloid deposits in vascular walls (black arrowheads) and glomeruli (white arrowheads) (c) show yellow to green birefringence under polarized light (d). Note that AA amyloid in chicken (c, d) has stronger staining than that in the cow (a, b).

The potassium permanganate method has been used for amyloid typing. In this method, the yellow to green birefringence by Congo red staining is attenuated after potassium permanganate treatment in AA, whereas the staining is retained in AL.²⁹ However, AA in some animal species is resistant to potassium permanganate treatment, and potassium permanganate–sensitive AL has also been reported.¹¹¹ Therefore, its use is considered unreliable.

Thioflavin S, a fluorescent dye, has also been used as a specific labeling method for amyloid fibrils.^10,98 Thioflavin T is commonly used for quantification of amyloid fibrils in vitro, using a fluorescence spectrophotometer.¹⁵ It can also be used for amyloid staining on tissue specimens using a fluorescent microscope.¹⁰⁰

Transmission Electron Microscopy

Amyloid fibrils are ultrastructurally defined as unbranched fibrils approximately 10 nm in diameter.^137,161,277 Some amyloids that are negative for Congo red can be confirmed by electron microscopy.²¹⁷

Immunohistochemistry

Immunohistochemistry is a useful tool for determining amyloid precursor proteins, but it is necessary to validate antibody cross-reactivity when applied to proteins of different animal species.²⁰³ It should be noted that inter- and intra-species variations (polymorphisms) in the amino acid sequence of the target antigen may be associated with the amyloidogenicity of the protein. Protein databases, such as the National Center for Biotechnology Information (NCBI, https://www.ncbi.nlm.nih.gov/), are useful for comparing amino acid sequences between species and estimating the antigenic affinity to the antibody and amyloidogenicity of the protein.

In some amyloids, it may be difficult for antibodies to bind to the epitope because of the conformational changes in the native structure. In such cases, denaturation with formic acid is effective for antigen retrieval. False-negative results may be obtained if the immunoreaction-targeted amyloidogenic regions are poorly conserved.^124,148 In such cases, it is advisable to use multiple antibodies targeting different regions of the protein, including nonamyloidogenic regions, which can be predicted by using a structural prediction software program.^70,265 For instance, AL amyloid fibrils are composed of an immunoglobulin variable domain, and thus, antibody targeting the C-terminal constant domain yields better immunohistochemical results.^200,239

Positive immunolabeling does not necessarily indicate that the target antigen is an amyloid. As mentioned earlier, many amyloid signature proteins colocalize with amyloids, and it is important not to misinterpret amyloid signature proteins as amyloids. Also, nonamyloid native amyloid precursor proteins may be detected by immunohistochemistry. Because amyloid is resistant to proteolysis, enzymatic treatment with actinase or proteinase K prior to primary antibody sensitization may differentiate amyloid from its precursor protein.^172,188,268

Antibodies for detecting specific protein conformational changes or conformers, such as oligomers and fibrils, are commercially available for some proteins.²⁷ Antibodies for detecting proteins with posttranscriptional modifications, such as phosphorylation, are also available.²⁷ Western blotting should be performed for antibody validation to confirm antigenicity and specificity for conformational posttranscriptional changes.

Mass Spectrometry

Mass spectrometry comprehensively analyzes peptides and protein constituents based on their molecular weights and charges.¹⁴¹ However, it relies on currently available protein databases. Consequently, animal proteins not registered in the database, mostly of nondomestic species, or whose exact amino acid sequence differs from that of the registered database because of variations (polymorphisms), are often difficult to identify. In such cases, de novo sequencing validation is necessary.⁹⁷ Also, analytical techniques should consider the various potential modifications of proteins.^36,122

For mass spectrometry–based amyloid analysis, it is important that the sample is selectively collected from amyloid deposits in the tissue specimens. Laser microdissection is used to precisely collect samples from the region of interest on a tissue section. Laser microdissection followed by liquid chromatography-tandem mass spectrometry provides a list of peptides that comprise the proteins in the deposits.¹⁴¹ This technique is useful for amyloid typing in humans and animals.^{112,124,161,178,211} If the area of the amyloid deposit is sufficiently large (>100,000 µm2), it can be manually dissected under a stereomicroscope.^148,170,224 The advantage of manual dissection is that amyloid can be collected from regular glass slides, and no expensive equipment is necessary. Proteomic analysis can also be performed using archived, stained tissue slides.¹⁷⁰ As mentioned above, amyloid signature proteins such as ApoE and ApoA-IV are co-deposited with amyloid fibrils. The detection of multiple amyloid signature proteins by mass spectrometry can validate the accuracy of tissue dissection.

Classification of Amyloidosis

To date, 21 amyloid precursor proteins have been identified in animals (Table 1). Among these, ameloblastin, α-S1-casein, α-S2-casein, calcitonin receptor-stimulating peptide 1 (CRSP1), and lipopolysaccharide-binding protein have been reported only in animals, and others have also been reported in humans.²⁴ Some amyloid deposition syndromes are of unknown clinical significance, as discussed below.

Amyloid deposition can occur in multiple organs when the precursor is a serum protein, resulting in systemic amyloidosis. Amyloid deposition confined to a specific organ or lesion area (e.g. tumor) is referred to as localized amyloidosis. Some amyloids, namely AA and AL, may present as either systemic or localized amyloidosis. Most localized amyloidoses are associated with neoplastic diseases and/or aging. However, the clinical significance of amyloid deposition in some forms of localized amyloidosis remains unclear.

Serum AA

Animals express up to four SAA isoforms, SAA1 through SAA4, of which SAA1 is involved in AA amyloidosis.^122,168,242 AA amyloidosis is the most common systemic amyloidosis in animals and has been reported in various mammalian^{9,60,112,121,137,142,155,175,195,223,262,278} and avian species.^{35,166,177,178,189} As an exception, rats do not develop AA amyloidosis because they do not express full-length SAA.¹⁵³ AA amyloidosis is commonly a systemic disease, but localized conditions such as amyloid arthropathy in chickens have been reported.^121,122

The precursor protein SAA is an acute-phase protein synthesized in the liver in response to cytokines such as interleukin-6.²¹⁴ Amyloid fibril formation is commonly triggered by supersaturation of circulating SAA associated with persistent inflammation.²⁶⁹ However, cases without apparent underlying diseases or familial conditions due to SAA mutations have also been reported. Familial AA amyloidosis has been reported in some canine and feline breeds, including Shar-Pei,²²⁵ Bracco Italiano,⁹⁵ Siamese, and Abyssinians.^20,262

Amyloid deposits can be found in vessel walls and interstitium throughout the body. In the kidney, the most commonly affected organ, severe amyloid deposition in glomeruli causes nephrotic syndrome (Fig. 3a). Diffuse deposition in the perisinusoidal space and the vascular walls is commonly observed in the liver (Fig. 3b). In the spleen, diffuse deposition in the perifollicular and perivascular areas can be seen (Fig. 3c). The lamina propria is the predominant location of amyloid deposition in the gastrointestinal tract (Fig. 3d). In addition, amyloid deposition can be observed in the vascular walls and interstitium of the pancreas, reproductive organs, endocrine organs (Fig. 3e), and other tissues (Fig. 3f). Although AA deposition in the nervous system is extremely rare, peripheral nervous system involvement has been reported in flamingos (Fig. 3g).¹⁸⁹

Figure 3.

Histologic features of AA amyloidosis in animals. Hematoxylin and eosin. (a) Kidney, dog. Glomeruli with mesangial amyloid deposits. (b) Liver, cat. Severe amyloid deposits in the perisinusoidal space. (c) Spleen, mouse. Severe amyloid deposits surrounding the white pulp. (d) Small intestine, cat. Amyloid deposits replacing the lamina propria. (e) Thyroid gland, microminipig. Amyloid deposits in the interfollicular stroma. (f) Heart, flamingo. Amyloid deposits in the arterial wall (arrowheads). (g) Peripheral nerve, flamingo. Focal amyloid deposits among the nerve fibers (arrowhead). (h) Kidney, cheetah. Amyloid deposits in the inner medullary interstitium. (i) Synovium, chicken. Amyloid deposits in the interstitium (arrowhead).

Deposition patterns of AA can vary among animal species and individual cases. For instance, glomerular deposition is rare, and medullary deposition is predominant in felids (Fig. 3h).^195,223 Atypical cases in cows have been reported in which renal deposition is almost absent, and deposition is predominant in the liver.¹⁶⁵ In experimentally induced murine AA amyloidosis models, amyloid deposition is relatively rare in the glomeruli and is often more prominent in the renal medulla.^99,267

AA amyloidosis is the primary differential diagnosis for systemic amyloidosis in animals. Immunohistochemistry using anti-SAA antibodies confirms the diagnosis. Commercially available anti-human SAA monoclonal antibodies (clones mc1 and 115) have very low cross-reactivity with animal AA. The polyclonal anti-human SAA antibody PAA885Hu01 (Cloud-Clone Corp., Houston, TX) is useful for detecting AA in animals. There is a highly conserved region in the SAA protein among various animal species⁵⁸; thus, antibody targeting this sequence is recommended.⁹⁹

Transmission of AA amyloidosis has been demonstrated in various experimental animals.^{143,162,167,171} Intravenously, intraperitoneally, or even orally administered exogenous AA is thought to act as a seed in the recipient and promote nucleation-dependent polymerization of the host SAA.¹⁴³ Transmission of AA amyloidosis has been shown to occur between different species.^39,231 In addition, experimental studies have shown that AA can be transmitted by oral ingestion.¹⁶⁸ A high incidence of AA amyloidosis has been reported in flocks of chickens,¹⁷¹ cheetahs,²⁸³ and sheltered cats,⁵¹ suggesting that horizontal transmission may occur between animals. Recent detailed structural analysis of amyloid fibrils using cryo-electron microscopy has shown that the N-terminal structures of human and murine AA fibrils are very similar, which may contribute to the stability of the amyloid fibrils and seeding.¹³⁶ Detailed risk analyses are necessary to evaluate the potential transmission of AA under nonexperimental conditions. Further information on amyloid transmission is provided in another review article.¹⁶⁸

Although AA amyloidosis is a systemic disease, a localized condition known as amyloid arthropathy has been described in chickens (Fig. 3i).^132,134 Amyloid arthropathy is secondary to arthritis caused by Enterococcus faecalis or Mycoplasma synoviae infection in the brown layers.^50,235 It is unclear whether the deposited AA is derived from circulating or locally produced SAA, although a previous study reported that naive and Lipopolysaccharide-stimulated fibroblast-like synoviocytes isolated from healthy chicken joints produce SAA.²⁶⁰ Chicken amyloid arthropathy develops into systemic amyloidosis as the disease progresses^126,133; thus, it is likely an initial lesion of systemic amyloidosis rather than localized amyloidosis.

Immunoglobulin Light Chain

The immunoglobulin light chain can form amyloid fibrils (AL), resulting in systemic or localized amyloidosis.^67,271 AL amyloidosis is associated with clonal proliferation of plasma cells that produce immunoglobulin light chains with the same variable domain sequence. Amyloid deposits are composed of either kappa or lambda immunoglobulin light chains produced by monoclonal plasma cells, which can be detected by immunohistochemistry or mass spectrometry. However, immunohistochemistry may produce negative results if the antibody does not recognize the specific conformation and the neighboring constant domain.¹¹¹ Therefore, it is advisable to use multiple antibodies targeting different constant domains of both kappa and lambda light chains.^90,111 AL amyloidosis in animals is commonly localized in association with a plasma cell tumor. Systemic AL amyloidosis is rare in animals and has only been reported in a horse with multiple myeloma¹¹⁸ and a cow with bovine leukocyte adhesion deficiency.²⁵¹

Transthyretin

Transthyretin (TTR), also known as prealbumin, is a plasma transport protein that is mainly produced in the liver and plays a role in the transport of thyroxine (T4) and retinol (vitamin A). TTR amyloidosis has been described in vervet monkeys (Chlorocebus pygerythrus).^29,176 Interestingly, vervet monkeys harbor an amino acid substitution at amino acid 122 of the TTR protein (Ile122) compared to other primates (Val122).²⁵⁹ Several types of TTR mutations associated with familial forms of TTR amyloidosis have been reported in humans. The Ile122 allele, the most common TTR mutation in the United States, causes late-onset cardiac amyloidosis.¹⁰² The clinical manifestations and pathology of TTR amyloidosis in vervet monkeys are comparable to those in the human disease. Almost half of vervet monkeys over 14 years of age show signs of cardiac dysfunction, such as arrhythmia, increased cardiothoracic ratio on radiography, increased plasma atrial natriuretic peptide concentration, and reduced ejection fraction.²⁵⁹ Amyloid deposits are observed in the vascular walls and interstitium of the heart and, to a lesser degree, in other organs, including the intestines, kidneys, lungs, tongue, and adipose tissue (Fig. 4a).^29,259

Figure 4.

Histologic features of systemic non-AA amyloidosis in animals. Hematoxylin and eosin. (a) Transthyretin amyloidosis, heart, vervet monkey. Amyloid deposits in the myocardial interstitium. (b) Apolipoprotein A-II amyloidosis, kidney, mouse. Glomeruli with multinodular amyloid deposits. (c) Apolipoprotein A-IV amyloidosis, kidney, cotton-top tamarin. Amyloid deposits in glomerular mesangium and tubular interstitium. (d) Apolipoprotein C-III amyloidosis, kidney, lion. Amyloid deposits replace the outer medulla. (e) EGF-containing fibulin-like extracellular matrix protein 1 amyloidosis, liver, Tsushima leopard cat. Amyloid deposits in the arterial wall (arrowheads). (f) Fibrinogen Aα-chain amyloidosis, kidney, Japanese squirrel. Amyloid deposits replace the glomeruli.

Apolipoprotein A-II

ApoA-II is the second most abundant serum high-density lipoprotein and is mainly produced by hepatocytes. Inbred mouse strains spontaneously develop systemic ApoA-II amyloidosis with aging in the absence of an increase in serum ApoA-II concentration.⁸⁶ ApoA-II amyloid deposits affect many extracerebral organs, including the kidney, liver, spleen, heart, lung, gastrointestinal tract, tongue, and skin. Although the prevalence and development of this disease differ among mouse strains, several studies have reported that aged wild-type C57BL/6 mice originating from the Jackson Laboratory (C57BL/6J) exhibit high incidence and progressive organ dysfunction.^22,135,222 Glomerular amyloid deposition is associated with podocyte injury and glomerulosclerosis, resulting in albuminuria (Fig. 4b).

There are multiple alleles of murine Apoa2 gene (A1, A2, B, C, D, E, and F), of which A1 and C are associated with ApoA-II amyloidosis predisposition. Compared to wild-type C57BL/6J mice carrying the type-A1 Apoa2 allele, mice carrying the type-C Apoa2 allele, such as senescence-accelerated mouse-prone1 (SAMP1) mice exhibit more severe amyloid deposition throughout the body, whereas Algerian mouse (Mus spretus)-derived laboratory mice (SPRET/Ei mice) carrying the type-F Apoa2 allele are resistant to amyloid deposition.^119,221 In addition, genetic analysis of the less amyloidogenic A/J mouse and SAMP1 strains identified 2 susceptible loci in the telomeric regions of chromosomes 4 and 19.⁷⁶ An experimental study has shown that administration of tissue-extracted ApoA-II amyloid drastically shortens the period to disease onset.⁸⁵ ApoA-II amyloidosis was induced in young mice reared in the same cage as old mice that developed severe ApoA-II amyloidosis.²⁷⁶ Transmissible amyloid seeds were detected from feces and milk of amyloid-laden mice.^129,276 The mechanism by which aging is involved in the progression of ApoA-II amyloidosis has yet to be elucidated.

Apolipoprotein A-IV

ApoA-IV amyloidosis is an uncommon form of systemic amyloidosis, in which ApoA-IV–derived amyloid accumulates in multiple organs.^40,147 This condition has not been observed in animals except in one case report of a cotton-top tamarin (Saguinus oedipus).²²⁴

ApoA-IV amyloidosis primarily affects the heart and kidneys in humans, showing distinctive signs of gradually worsening cardiac and renal functions. Notably, amyloid deposition in the kidneys tends to be severe in the medulla and infrequent in the glomeruli.^147,167 In the cotton-top tamarin, amyloid was deposited predominantly in the glomeruli (Fig. 4c). In addition to the kidneys, severe amyloid deposition was observed in the liver, spleen, ovaries, adrenal glands, and intestinal lamina propria of the tamarin, which has not been documented in human patients with ApoA-IV amyloidosis.^173,224 Because the distribution of amyloid is similar to that of AA amyloidosis in callitrichids,¹⁴² immunohistochemistry is necessary to rule out AA amyloidosis.

It should be noted that ApoA-IV is also an amyloid signature protein in other types of amyloidosis. Therefore, the diagnosis of ApoA-IV amyloidosis should not be based only on the ApoA-IV-positive reaction by immunohistochemistry; quantitative evaluation based on mass spectrometry is essential for diagnosing ApoA-IV amyloidosis. In humans, the diagnostic criteria for ApoA-IV amyloidosis include a high number of ApoA-IV peptides detected by mass spectrometry and the absence or low levels of other amyloidogenic proteins.³⁶ The diagnosis of animal ApoA-IV amyloidosis should also be based on this criterion.

Apolipoprotein C-III

Apolipoprotein C-III (ApoC-III) is a protein involved in triglyceride-rich lipoprotein metabolism.²⁰² ApoC-III amyloidosis, in which ApoC-III is the precursor protein, is a rare disease and has only been reported in one report each for humans and animals. In humans, the D25V mutation of ApoC-III is implicated in its etiology.²⁶¹ In animals, ApoC-III amyloidosis is reported in white lions (Panthera leo), which, unlike humans, have no mutation in the APOC3 gene.¹²⁵ It has been suggested that ApoC-III amyloidosis in lions may be age-related or involve genetic background factors.¹²⁵ Histologically, amyloid deposits in the systemic vascular walls and interstitial tissues of the affected white lions (Fig. 4d). Deposition is particularly severe in the kidneys and is confined to the interstitium of the extramedullary zone. The pattern of renal amyloid deposition differs from that of AA amyloidosis, which involves the glomerulus; however, it may be difficult to differentiate them without immunohistochemistry. An anti-human ApoC-III polyclonal antibody (Bioss, Woburn, MA) can be used for immunohistochemistry.¹²⁵

EGF-Containing Fibulin-Like Extracellular Matrix Protein 1

EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) amyloidosis has been reported in humans²⁵⁴ and a Tsushima leopard cat (Prionailurus bengalensis euptilurus).¹⁶⁰ Interestingly, in humans, the C-terminal region of EFEMP1 is involved in amyloid formation, whereas in the Tsushima leopard cat, the N-terminal region of EFEMP1 is thought to be involved. Amyloid is mainly deposited in venous walls of humans, whereas it was mainly deposited in the arterial walls of the Tsushima leopard cat, perhaps reflecting different amyloidogenic regions of the protein (Fig. 4e). EFEMP1 amyloidosis in the Tsushima leopard cat can be histologically differentiated from AA amyloidosis by the lack of amyloid deposition in the renal tubular interstitium and severe deposition in the submucosal tissue rather than the lamina propria of the gastrointestinal tract. EFEMP1 is produced locally in the vascular walls, resulting in amyloid deposition in blood vessels and perivascular stroma. Therefore, it can also be considered localized amyloidosis in systemic vessels rather than systemic amyloidosis.²⁵³

Fibrinogen Aα-Chain

Fibrinogen Aα-chain amyloid (AFib) causes a systemic disease in animals and humans.^69,279 In animals, AFib amyloidosis has been reported in aged Japanese squirrels (Sciurus lis).⁹⁷ In humans and squirrels, the amyloid is exclusively deposited in the glomeruli, resulting in renal failure (Fig. 4f).^14,97 Amyloid deposits may also be seen in other organs in severely affected cases.^14,97 Although the precursor protein plays a role in coagulation, AFib amyloidosis is not associated with coagulopathy in humans.⁶³ AFib amyloidosis can be differentiated from AA amyloidosis, which involves the tubulointerstitium, perivascular space, and glomeruli. As only approximately 100 amino acid residues at the C-terminus of AFib are involved in amyloidogenesis, antibodies that recognize this region should be used for immunohistochemistry. For immunohistochemistry, an anti-human AFib monoclonal antibody (clone sc-398806) is recommended.⁹⁷

Apolipoprotein A-I

Apolipoprotein A-I (ApoA-I) amyloidosis is hereditary systemic amyloidosis or acquired localized arterial amyloidosis in humans.^7,37,164 In animals, localized amyloidosis occurring in the pulmonary vasculature has been reported in dogs.^49,108,215 The incidence increased with age, occurring in 22% of dogs older than 10 years.²¹⁵ Since there was no effect of ApoA-I mutation, sex, breed, or concomitant diseases, it is speculated that abnormal metabolism of ApoA-I associated with aging is involved in the pathogenesis of the disease. However, no studies on canine ApoA-I amyloidosis have been reported since the 1990s, and the detailed pathogenesis of this disease remains unknown. Since ApoA-I also has the properties of an amyloid signature protein, this should be considered when diagnosing amyloidosis by immunohistochemistry or mass spectrometry.¹⁶⁰

Islet Amyloid Polypeptide

IAPP, also known as amylin, is a hormone linked to type 2 diabetes, which consists of 37 amino acids after posttranslational processing of its original pre-pro-peptide. IAPP-derived amyloid deposition in the pancreas is reported in various animal species, including monkeys,⁴¹ dogs,^184,185 and cats.²⁸⁵ Clinical symptoms of IAPP amyloidosis-affected animals have not been described, and amyloid deposits are often found incidentally at autopsy.⁸¹ Amyloid in islets affects beta cells and the vasculature (Fig. 5a).²⁷

Figure 5.

Histologic features of localized amyloid deposition in animals. (a) Islet amyloid polypeptide amyloidosis, pancreas, cat. Amyloid deposits in the islets. Hematoxylin and eosin (HE). (b) Insulin amyloidosis, pancreas, degu. Amyloid deposits in the islet. HE. (c) Plasmacytoma, rectum, dog. Amyloid deposits within the tumor (arrowheads). HE. (d) Amyloid-producing ameloblastoma, mandible, dog. Amyloid deposits in tumor tissue. HE. (e) C-cell carcinoma, parathyroid, cat. Amyloid deposits in tumor tissue. HE. (f) Lipid-rich mammary carcinoma, mammary gland, dog. Amyloid deposits in the interstitium. HE. (g) Skin, dog. Amyloid deposits surrounding hair follicle (arrowheads). Congo red. (h) Amyloid deposition, mammary gland, cow. Amyloid deposits corresponding to corpora amylacea (arrowheads). HE. (i) Amyloid deposition, mammary gland, rat. Needle-shaped amyloid on the surface of corpora amylacea (arrowheads). The inset shows higher magnification. HE.

More than 70% of feline and human patients with type 2 diabetes have amyloid deposits in the pancreatic islets.^{93,183,205,272} Diabetic cats exhibit reduced islet size, beta cell loss, and mild inflammation.²⁸⁵ A recent study investigated the amyloidogenic properties of feline IAPP and its positive relationship with feline diabetes and pancreatitis.¹¹⁰ Feline IAPP is highly prone to fibril formation, similar to human diabetes-associated IAPP. Elevated plasma IAPP levels were detected in feline diabetes patients.¹¹⁰ One functional role of IAPP is to provide satiety. IAPP is stored in the secretory granules of beta cells. In type 2 diabetes, secretion of IAPP and insulin demand is elevated, increasing local concentration of IAPP, which may result in amyloid depositions.⁶⁸

There are variations in the amino acid sequence of IAPP among animal species. The presence of 3 prolines in the amino acids 24–29, such as those in IAPP of the rat and mouse, prevents its aggregation, and thus rats and mice do not develop pancreatic amyloidosis. Other species that are known to be resistant to pancreatic amyloidosis are guinea pig, degu (Octodon degus), cow, golden lion tamarin (Leontopithecus rosalia), alpaca (Vicugna pacos), and common bottlenose dolphin (Tursiops truncatus).^54,158 Cases of naturally occurring pancreatic amyloidosis without reported prediabetic and/or diabetic status have been reported in nonhuman primates,²⁴ domestic cats,²⁴ cougars (Felis concolor),¹⁰⁹ ocelots (Leopardus pardalis),¹¹⁵ and raccoons (Procyon lotor).^24,280 Deposition of IAPP amyloid has been reported in cases of insulinomas in dogs.^184,185 Based on an in vitro study, sheep and goats seem resistant to developing type 2 diabetes despite the presence of amyloid deposits in their pancreas.¹⁵⁷

Insulin

Insulin amyloidosis is a phenomenon in which amyloid fibrils derived from insulin are deposited in pancreatic islets (Fig. 5b).²³⁷ In humans, iatrogenic pathology is common and is caused by repeated insulin administration to the same site in the subcutaneous tissue of diabetic patients. This is the preeminent predisposing factor for local amyloid deposition.^6,237 In animals, amyloid deposition is commonly observed in the pancreatic islets of aging degus (Fig. 5b).²³³ Unusually in this species, the amyloid fibrils appear to be composed of insulin itself, rather than IAPP as observed in the other species studied to date.²⁷¹ The onset of the disease in degus seems to be age-related.⁸⁴ There are differences in the amino acid sequence of insulin among degus and other animals, including humans, which may account for the structural differences in the protein.⁸⁴

Amyloid β

Amyloid β (Aβ) is produced by the cleavage of APP, an integral membrane protein expressed in neurons and other cells. Several Aβ subtypes are produced according to the cleavage site. The major subtypes are Aβ40, Aβ42, and Aβ43.²⁴³ Aβ deposits can be found in the neuropil of the cerebral gray matter and vascular walls of the meninges and cerebrum in aged individuals (Fig. 6a, b). Aβ deposition has been reported in many animal species with high amino acid sequence identity to human Aβ, such as primates, dogs, bears, sea lions, camels, and birds.²⁸² In such species, Aβ deposits can be detected immunohistochemically using anti-Aβ antibodies raised against human Aβ with formic acid antigen retrieval.^30,243

Figure 6.

Central nervous system amyloid deposits and related histopathologies in animals. (a) Cerebral meninges, dog. Amyloid β deposits in the arterial wall (arrowheads). Hematoxylin and eosin (HE). (b) Cerebral cortex, dog. Amyloid β deposits in the capillary wall (arrowhead). HE. (c) Cerebral cortex, squirrel monkey. Amyloid plaques (black arrowheads) in the neuropil have central cores (mature plaques). The inset shows autofluorescence by violet excitation (red arrowhead). Note that the fluorescence of the plaque is different from that of lipofuscin (white arrowheads). HE and unstained (inset). (d) Cerebral cortex, cat. Neurofibrillary tangles in neurons. Gallyas-Braak stain. (e) Cerebral cortex, cat. Hyperphosphorylated tau accumulation in neurons. Immunohistochemistry for hyperphosphorylated tau. (f) Scrapie, obex, sheep. Vacuolar degeneration in the neuropil and neuronal soma (arrowhead). HE.

Aβ deposits in the neuropil are called “senile plaques” and are further classified into mature, diffuse, and other types. Mature plaque, which is also called “classic cored plaque,” has a central core that is Congo red-positive (Fig. 6c), while diffuse plaques are Congo red-negative, suggesting that these two types have different fibrillation properties and may be sequential lesions of a maturation process.²¹⁶ Periodic acid-methenamine silver staining is useful for detecting both types of plaques.²⁸¹ Senile plaques are associated with Alzheimer’s disease in humans, and a significant number of mature plaques surrounded by dystrophic neurites are formed in the patient’s brain. Mature plaques are rarely observed in animal brains, and the clinical significance of senile plaques in animals is yet to be elucidated.¹⁹² Most Aβ plaques in animals cannot be detected in hematoxylin and eosin–stained sections, and immunohistochemistry or silver staining is necessary. However, Aβ lesions in squirrel monkeys (Saimiri boliviensis)¹⁸² and APP/PS1 transgenic mice⁶¹ exhibit blue-white autofluorescence under blue-violet excitation and can be detected without labeling using fluorescence microscopy (Fig. 6c).

Vascular wall Aβ deposits are involved in cerebral amyloid angiopathy. Aβ deposits are detected in arteries, arterioles, veins, venules, and capillaries using immunohistochemistry. In aged dogs, capillary deposits are distributed multifocally in the cerebral cortex.³¹ Cerebral amyloid angiopathy has been associated with microhemorrhage and white matter changes in humans and dogs.^33,34,57,257

The sequence of Aβ in felids is 1 amino acid different from human Aβ at the N-terminus (felid-type Aβ).^31,33,282 Aged felids develop unique diffuse granular deposits in the cerebral cortex that can be detected by immunohistochemistry using anti-human Aβ antibodies raised against the C-terminus.⁵³ Also, intraneuronal Aβ accumulation has been reported in domestic cats.^31,232 Amino acid sequence of Aβ in mice and rats (rodent-type Aβ) differs by 3 amino acids from the human Aβ, and these animals do not develop spontaneous amyloid deposits in their brains.

Tau

Tau is a microtubule-associated protein that functions in the assembly and stabilization of microtubules in the neuronal axons. As a simplification of the 6 known tau isoforms, 2 major splicing isoforms are distinguished by the number of repeats in the microtubule-binding domain: 3-repeat (3R) tau and 4-repeat (4R) tau.²⁵² Intracellular aggregation of misfolded tau protein is responsible for a group of neurological diseases in humans called “tauopathies,” which includes Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration, chronic traumatic encephalopathy, and others. Affected cells (neurons, astrocytes, and oligodendrocytes), aggregated tau isoforms, and distributions differ between these diseases.²⁵² As described before, misfolded tau can be found extracellularly upon cell death or in the synaptic cleft, and its cytotoxity is due to aggregation; therefore, the misfolded tau has recently been classified as an amyloid.^24,230

Alzheimer’s disease is the most prevalent tauopathy in humans and is histopathologically characterized by neurofibrillary tangles (NFTs), which are fibrillar aggregates of hyperphosphorylated tau protein in the cerebral neurons. NFTs are composed of both 3R and 4R tau. NFT is detected by Gallyas-Braak silver staining (Fig. 6d) and is immunohistochemically positive using anti-hyperphosphorylated tau antibodies such as clones AT8 (Ser202, Thr205) and AT100 (Thr212, Ser214; Fig. 6e). Aged felids, including domestic cats, cheetahs, and leopard cats, are known to develop significant numbers of NFTs comparable to those in Alzheimer’s disease.^{31,32,53,75,83,226,232} NFTs have been reported in other animal species, including monkeys and pinnipeds.^45,198,246 Hyperphosphorylated tau-positive neurons have been observed in the brains of headbutting bovids, which may be associated with chronic traumatic encephalopathy, a neurological condition described in American football players and people who have experienced repeated head trauma.³ Misfolded hyperphosphorylated tau and its spreading occur predominantly in stages 3 and 4 of human chronic traumatic encephalopathy (in Dr. McKee’s staging scheme).^52,152 NFTs are rarely found in the brains of aged dogs (personal communication by an author, JKC). In addition to NFTs, hyperphosphorylated tau aggregates in astrocytes, which are characteristic of progressive supranuclear palsy and corticobasilar degeneration in humans, have been reported in aged cynomolgus monkeys (Macaca fascicularis).^117,258 Hyperphosphorylated tau aggregates are also found in oligodendrocytes of aged felids, pinnipeds, and monkeys.^31,246,258 The clinical significance of tauopathy in animals is yet to be elucidated.

Wild-type mice do not develop NFTs, which is likely attributable to the expression patterns of the tau isoforms. Both 3R and 4R isoforms are expressed in the adult human brain, whereas only the 4R isoform is expressed in the mouse brain.²⁴⁸ The ratio of 3R to 4R isoforms expressed in animal brains varies among species.^31,104,246

α-Synuclein

α-Synuclein is mainly expressed in the axon terminals of presynaptic neurons and plays a role in neurotransmitter release.²³⁸ In humans, intracellular aggregation of misfolded α-synuclein protein is involved in Parkinson’s disease, dementia with Lewy bodies, and multiple-system atrophy, which are collectively called “synucleinopathies.” Neuronal inclusions composed of misfolded α-synuclein, known as Lewy bodies, are the characteristic lesions of Parkinson’s disease and dementia with Lewy bodies. Lewy bodies have not been reported in animals.

Aggregation of α-synuclein can be induced in wild-type mice and monkeys by intracerebral injections of α-synuclein extracted from the brains of human patients with synucleinopathy, suggesting the prion-like nature of α-synuclein.^149,206 In addition, α-synuclein aggregates have been reported in transgenic mouse strains that overexpress the human hyperphosphorylated-tau protein.^244,245 These experimental studies suggest that native mouse and monkey α-synucleins have the potential to aggregate by seeding with exogenous amyloid proteins. Seeding is thought to be involved in intracerebral propagation of misfolded α-synuclein.^139,179,191

In veterinary medicine, misfolded α-synuclein occurs in aged horses affected with pituitary pars intermedia dysfunction.^55,151 Higher levels of α-synuclein have been detected by McFarlane et al¹⁵¹ in pituitary pars intermedia dysfunction horses. Seeding experiments and electron microscopic studies demonstrated the presence of misfolded α-synuclein in horses with pituitary pars intermedia dysfunction compared to aged and young horses.⁵⁵ Several laboratories have studied the aggregation kinetics (or propensity to misfold) of α-synuclein peptides designed from amino acid sequences of animal species.^56,220 Further studies are needed to determine whether spontaneous aggregation of α-synuclein occurs in additional animal species.

Prion Protein

Prion diseases or transmissible spongiform encephalopathies are neurodegenerative disorders in which the conformation of cellular prion proteins (PrP^C) becomes abnormal, and their aggregates accumulate in the brain, resulting in functional impairment.⁹⁴ Prion diseases have been considered protein misfolding disorders, but like other amyloidoses,¹⁷⁴ they have in vitro seeding activity and the ability to form fibrils and can be considered a type of amyloidosis in a broad sense.²⁸⁴ Prion diseases have been reported in primates, sheep, goats, minks, felids, camels, deer, cows, and other exotic ruminants.^190,227 Vacuolar changes and aggregation of misfolded prion protein (PrP^Sc) in the brain are histopathological characteristics regardless of species (Fig. 6f).

Conformational changes in PrP^C can be induced by the transmission of PrP^Sc, which is mostly the case in animals; by an inherited mutated prion gene (PRNP); or spontaneously in atypical cases.^4,73 In the brain, PrP^Sc deposits can be detected intracellularly (neurons and glial cells) or extracellularly using immunohistochemistry with formic acid and heat antigen retrieval.²⁶³ From a diagnostic perspective, amyloid plaques may be recognized on hematoxylin and eosin-stained sections; however, they are more easily detected by silver staining, Congo red staining, and most dramatically, by immunohistochemistry.^74,273

Scrapie is the oldest known prion disease and occurs in sheep and goats. Clinical manifestations include tremor and behavioral changes, but intense pruritus is the most characteristic clinical sign.^73,94 The incubation period for scrapie is 2–5 years.⁹⁴ PrP^Sc has been detected in the nervous system, pancreas, heart, skin, bladder, mammary gland, and saliva.^64,73 After oral uptake, pathogenic PrP^Sc crosses the intestinal mucosal barrier, replicates in gut-associated lymphoid tissues, and then spreads to the brain via neuronal or hematogenous pathways.^247,263 Atypical scrapie, which differs in pathological features compared to typical scrapie, has been reported.^{13,120,150,158} Although the distribution of PrP^Sc deposits in the brain varies among animal species and disease types, the medulla oblongata is the most consistent diagnostic region for transmissible spongiform encephalopathies, except in atypical prion diseases, which mainly involves cerebellum.^13,65 Atypical scrapie spontaneously occurs most commonly at 5 years of age and older and is thought to occur sporadically with age rather than by transmission.² The main clinical manifestations of atypical scrapie are ataxia and dyscoordination, but pruritus is rare.⁹⁴

Chronic wasting disease (CWD) is a prion disease found in captive and free-ranging Cervidae family members, mainly in North America, and eradication is a major challenge.⁹⁴ Although the detailed pathogenesis remains unknown, horizontal transmission is suspected; CWD-like spongiform encephalopathy can be induced by intracerebral inoculation of sheep PrP^Sc in elk.⁷⁹ Since the pathogenic prion protein (PrP^CWD) is detected in gut-associated lymphoid tissues,^228,234 prions may be shed into the environment via feces and saliva. In addition, CWD prions can remain pathogenic in soil for long periods of time, which may contribute to sporadic disease outbreaks.^106,107 PrP^CWD is found in various organs of affected animals, like scrapie prion.⁹⁴

Bovine spongiform encephalopathy is a prion disease that occurs in cattle and is associated with clinical signs such as tremors and abnormal gait of the hind limbs.⁹⁴ The incubation period of bovine spongiform encephalopathy is 2–8 years, and most cases occur at the age of 4–5 years.¹⁸¹ PrPSc accumulation is usually seen in the brain, but bovine spongiform encephalopathy prions may also be detected in the spinal cord, retina, adrenal glands, ileum, tonsils, bone marrow, peripheral nerves, ganglia, and muscle in late stages of the disease.^94,187

Distinct strains of prions have been identified and associated with different incubation periods, clinical signs, tissue tropisms, and host ranges.^11,145 In addition, host PRNP genotypes have been associated with a predisposition to resistance or susceptibility to prion disease.^2,94,190 For example, PRNP gene mutations are involved in the pathogenesis of atypical scrapie.^38,73 Variations in host genotypes and prion strains result in complex and diverse disease phenotypes, which is beyond the scope of this review.⁶⁵

Tumor-Associated Localized Amyloidosis

Amyloid deposits may occur in tumors that produce amyloid precursor proteins. In animals, tumor-associated localized amyloidosis has been reported in extramedullary plasmacytomas, amyloid-producing ameloblastomas, C-cell carcinomas, insulinomas (covered above in the IAPP section), and mammary gland tumors.

Plasmacytoma

In extramedullary plasmacytomas, monoclonal immunoglobulin (M protein) produced by neoplastic cells may form amyloid.⁵ As described previously, in systemic AL amyloidosis, amyloid is derived from free light chains in the serum, resulting in vascular and perivascular amyloid deposits.⁵ Conversely, locally produced light chains form nodular amyloid deposits in plasmacytoma-associated localized AL amyloidosis (Fig. 5c).²⁷⁰ Amyloid deposits can also be seen in the vessels surrounding the amyloid nodules, but they are distinguishable from systemic amyloidosis because the vascular deposits disappear away from the central lesion.¹¹¹ Granulomatous inflammation characterized by multinucleated giant cells commonly accompanies localized AL amyloidosis.^111,116,204

Since AL amyloid is largely constituted from the variable domain of the light chain, diagnosis of AL amyloidosis by immunohistochemistry is challenging as described in the AL amyloidosis section above.¹¹¹ Examination of the protein components by mass spectrometry supports the diagnosis.¹¹¹ Practically, morphological diagnosis of plasmacytoma, supported by immunohistochemistry for plasma cell markers such as MUM1,⁸⁰ strongly suggests that the locally deposited amyloids are AL. Immunoglobulin light chains are classified into kappa and lambda light chains, but all localized AL amyloidoses in animals identified to date are derived from the lambda light chain.^{80,111,116,138,204}

It has been suggested that AL amyloid is toxic to tumor cells.²⁷⁰ In some cases, the tumor cells die out, and only the amyloid nodule is left.^{111,116,138,204} In humans, although it is not known whether amyloid-induced tumor cell death is involved, plasma cell tumors with localized AL amyloidosis has a better prognosis than plasma cell tumors without amyloid.¹⁴⁶ In the author’s experience, cutaneous plasma cell tumors with amyloid in dogs have a good prognosis, although multiple lesions may develop. Plasma cell tumors with amyloid in visceral organs, mostly reported in cats,²¹⁹ have a poor prognosis because of organ dysfunction.^240,249 Investigating the prognostic impact of amyloid deposition on tumor outcomes in animals may provide clinically useful information.

Amyloid-Producing Ameloblastoma

Amyloid-producing ameloblastoma has been reported in cats,^19,43,62,186 dogs,^62,89,186 a goat,¹⁴⁰ a prairie dog (Cynomys ludovicianus),¹²⁸ and a Bengal tiger (Panthera tigris tigris).¹¹⁴ This tumor in animals used to be called amyloid-producing odontogenic tumor but was renamed “amyloid-producing ameloblastoma.”⁴⁴ Histologically, these tumors are characterized by irregular nests, islands, and strands of proliferating odontogenic epithelium supported by varying amounts of fibrous stroma with moderate to severe amyloid deposits (Fig. 5d).¹⁴⁸

Amyloid-producing ameloblastoma was previously considered equivalent to calcifying epithelial odontogenic tumor in humans; however, the current consensus is that amyloid-producing ameloblastoma is not analogous to calcifying epithelial odontogenic tumor.^18,101 In calcifying epithelial odontogenic tumor, odontogenic ameloblast-associated protein has been identified as the amyloid precursor protein.²⁴ However, ameloblastin is a major component of amyloid deposits in amyloid-producing ameloblastoma by mass spectrometry–based proteomic analysis, and immunohistochemistry has shown evidence of the presence of the N-terminal region of ameloblastin in amyloid deposits in both cats and dogs.^87,89,148 Ameloblastin is a protein found in the enamel, the outer layer of the tooth, and is produced by differentiated dental epithelial cells known as ameloblasts.^105,163 It is necessary to select antibodies that react with the N-terminus of ameloblastin for its detection in tissue sections by immunohistochemistry.

C-Cell Carcinoma

Amyloid deposition occurs in 80% of human thyroid C-cell carcinomas, and calcitonin has been identified as the precursor protein.⁴⁶ On the other hand, amyloid deposition is uncommon in animal C-cell carcinomas and has been reported sporadically in dogs,^196,197 foxes,⁸⁸ sheep,²⁰⁷ bulls,¹⁷ and a cat (Fig. 5e).¹⁷⁰ CRSP1 was found to be the amyloid precursor protein in feline C-cell carcinomas.¹⁷⁰ Considering the high identity of CRSP1 among cats and canines, it is likely that CRSP1 also forms amyloids in canine and fox C-cell carcinomas.¹⁷⁰ In contrast, bovine calcitonin has amyloidogenic properties in vitro,²⁶⁶ and it is possible that the amyloid precursor protein of amyloid-producing C-cell carcinomas in ruminants is calcitonin, similar to that in humans.

Mammary Gland Tumors

Canine mammary tumors may be associated with localized amyloidosis characterized by diffuse to nodular amyloid deposits in the stroma (Fig. 5f).^250,255,264 Amyloid deposits should be differentiated from corpora amylacea, which form in the mammary gland ducts. Mass spectrometry–based proteomic analysis has identified α-S1-casein as the amyloid precursor protein.¹⁶⁹ Amyloid-producing canine mammary tumors overexpress α-S1-casein, and the N-terminal region is truncated in α-S1-casein within amyloid deposits, suggesting that α-S1-casein acquires amyloidogenicity through supersaturation-associated self-aggregation and proteolysis.^71,169 Given the propensity of various milk proteins to form amyloids in vitro,^{48,78,194,199,256} mammary tumor–associated amyloidosis may also occur in other species.

Amyloid Deposition of Unknown Pathological Significance

This section summarizes amyloid deposits of unknown pathological significance in animals.

Keratinic Amyloid Deposition in the Skin

Amyloid deposition is occasionally observed in hair follicle tumor’s stroma and around normal hair follicles in dogs (Fig. 5g).¹²⁴ Although this condition appears to correspond to keratinic primary localized cutaneous amyloidosis in humans,¹⁵⁶ its pathological significance remains unknown because of the negligible amount of amyloid deposition found in dogs. Keratin 5 has been identified as the precursor protein of amyloid formation.¹²⁴ However, the mechanism underlying how keratin 5 expressed in keratinocytes deposits under the basement membrane to generate amyloid fibrils is unknown. The amyloid deposits in these cases can be immunolabeled using the anti-keratin 5 monoclonal antibody clone XM26.¹²⁴

Amyloid Deposition in the Corpora Amylacea in Mammary Glands

Corpora amylacea are periodic acid-Schiff-positive spherical structures that may be observed in various organs.^{28,113,213,275} In 1854, Rudolph Virchow discovered iodine-reactive spherical structures in the brain and named them corpora amylacea, from which the term “amyloid (starch-like)” originated.¹³⁰ It should be noted, however, that the Latin term corpora amylacea, which means amyloid body, does not necessarily contain amyloid. In cattle,¹⁸⁰ rats,¹² and dogs,²⁵⁰ corpora amylacea formed in the mammary gland often contain amyloid; α-S2-casein has been identified as an amyloid precursor protein in cattle (Fig. 5h).¹⁸⁰

In the mammary glands of aged rats, needle-like amyloid deposits are observed on the surface of the corpora amylacea (Fig. 5i).¹⁷² Mass spectrometry–based proteome analysis has identified lipopolysaccharide-binding protein as a precursor protein of needle-like amyloid, and synthetic peptides derived from lipopolysaccharide-binding protein actually form amyloid in vitro.¹⁷² Inflammatory cell clusters are observed around needle amyloid deposits.

Although corpora amylacea were discovered long ago, their pathological or functional significance is still under debate. In recent years, the concept of “wasteosomes” has emerged.²⁰⁹ The mammary gland has a potentially high risk of protein misfolding owing to its high protein production and concentration. Indeed, many milk proteins, such as α-S1-casein and κ-casein, have amyloid-forming properties that are often cytotoxic.^42,170 Corpora amylacea (acting as wasteosomes) may have a protective function by trapping pathologically misfolded proteins within their glycan structures and safely metabolizing or releasing them. In fact, corpora amylacea in the human brain contain ubiquitinated waste products, which are thought to contribute to brain clearance systems by expelling them into the cerebrospinal fluid.^208,210

Amyloidosis in Vertebrates Other Than Mammalian and Avian Species

Amyloidosis in vertebrates other than mammalian and avian species is extremely rare, and many reports have failed to prove the presence of amyloid in histologically suspicious lesions. However, at least two papers have demonstrated amyloid deposition.^23,25 In the African tiger snake (Telescopus semiannulatus), massive amyloid (confirmed by congophilia, fluorescence of a luminescent-conjugated oligothiophene [h-FTAA] probe and transmission electron microscopy) was deposited in the interstitium and vessel walls of the spleen and testis.²³ Amyloid was negative on anti-SAA immunolabeling, and the amyloid precursor protein is unknown.²³ In the stingray (Bathytoshia centroura), amyloid-like structures were deposited in the renal mesangium.²⁵ Although deposits were negative for Congo red and thioflavin T, electron microscopy revealed amyloid-like fibrils.²⁵ Several other cases of suspected amyloidosis in vertebrates other than mammalian and avian species have been reported, but none have formally confirmed amyloid by additional methods, and these are not discussed further. Although there have been no known reports of amyloidosis in invertebrates, it is worth noting that bacteria, fungi, and insects (and even humans) use amyloid to achieve diverse biological functions (the so-called functional amyloid).^21,47

Conclusion and Perspectives

As the pathogenesis of amyloidosis differs depending on the amyloid precursor protein, amyloid typing is important to understand its pathogenesis. To date, 21 amyloid precursor proteins have been identified in animals. Some of these have been reported only in specific animal species and are likely to be associated with species-specific protein amino acid sequences and metabolism.^{84,97,161,224,259} In contrast, aging is a predisposing factor for amyloidosis across species.^{45,84,97,135,215,246,253} With the increasing longevity of captive animals, it is highly possible that novel amyloidoses will be found in the future. However, the significance of age-related amyloid deposition, such as whether it is a pathological change that causes organ damage and dysfunction or a physiological change associated with age-dependent accumulation of misfolded proteins, is often unclear in animals.²⁵³ Further comparative pathological studies of the amino acid sequence and nature of amyloids may enable an evolutionary understanding of physiological protein aggregation and protein misfolding diseases.

The authors hope that the diagnostic methods and classifications described here will help veterinary pathologists in diagnostic practice. Moreover, novel amyloids that are not listed here are likely to be discovered by veterinary pathologists. The classification of animal amyloidosis should be updated periodically by gathering more information on its pathogenesis and clinical features.

Footnotes

Acknowledgements

The authors thank Prof. Shinichiro Nakamura for providing HE-stained tissue images of the heart of a velvet monkey. The authors would like to acknowledge Naseem H. Alfadhl for putting together the initial summaries about the animal and experimental studies for the human IAPP section.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Tomoaki Murakami

James K. Chambers

References

Abramov

Potapova

Dremin

, et al. Interaction of oxidative stress and misfolded proteins in the mechanism of neurodegeneration. Life. 2020;10:101.

Acín

Bolea

Monzón

, et al. Classical and atypical scrapie in sheep and goats. Review on the etiology, genetic factors, pathogenesis, diagnosis, and control measures of both diseases. Animals. 2021;11:691.

Ackermans

Varghese

Williams

, et al. Evidence of traumatic brain injury in headbutting bovids. Acta Neuropathol (Berl). 2022;144:5–26.

Aguilar-Calvo

García

Espinosa

, et al. Prion and prion-like diseases in animals. Virus Res. 2015;207:82–93.

Al Hamed

Bazarbachi

, et al. Comprehensive review of AL amyloidosis: some practical recommendations. Blood Cancer J. 2021;11:97.

Ansari

Osmani

Matsangos

, et al. Current insight in the localized insulin-derived amyloidosis (LIDA): clinico-pathological characteristics and differential diagnosis. Pathol—Res Pract. 2017;213:1237–1241.

Arciello

Piccoli

Monti

DM.

Apolipoprotein A-I: the dual face of a protein. FEBS Lett. 2016;590:4171–4179.

Ayers

Paras

Prusiner

SB.

Expanding spectrum of prion diseases. Emerg Top Life Sci. 2020;4:155–167.

Barnett

JEF

Gilbertson

Arrow

, et al. Hepatic Amyloidosis in a chronically entangled grey seal (Halichoerus grypus). J Comp Pathol. 2022;199:1–7.

10.

Barton

Rogers

, et al. Inhalable thioflavin S for the detection of amyloid beta deposits in the retina. Molecules. 2021;26:835.

11.

Bartz

JC.

Prion strain diversity. Cold Spring Harb Perspect Med. 2016;6:a024349.

12.

Beems

Gruys

Spit

BJ.

Amyloid in the corpora amylacea of the rat mammary gland. Vet Pathol. 1978;15:347–352.

13.

Benestad

Sarradin

Thu

, et al. Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet Rec. 2003;153:202–208.

14.

Benson

MD.

Ostertag revisited: the inherited systemic amyloidoses without neuropathy. Amyloid. 2005;12:75–87.

15.

Biancalana

Koide

Molecular mechanism of Thioflavin-T binding to amyloid fibrils. Biochim Biophys Acta. 2010;1804:1405–1412.

16.

Birdwell

Levesque

Machiah

, et al. Clinicopathologic characteristics of pancreatic islet amyloidosis in the rhesus macaque (Macaca mulatta) and sooty mangabey (Cercocebus atys). J Med Primatol. 2022;51:155–164.

17.

Black

Capen

Young

DM.

Ultimobranchial thyroid neoplasms in bulls. A syndrome resembling medullary thyroid carcinoma in man. Cancer. 1973;32:865–878.

18.

Blackford Winders

Bell

Goldschmidt

Case report: amyloid—producing odontogenic tumor with pulmonary metastasis in a Spinone Italiano—proof of malignant potential. Front Vet Sci. 2020;7:576376.

19.

Bock

Hach

Baumgärtner

Oral masses in two cats. Vet Pathol. 2011;48:906–910.

20.

Boyce

DiBartola

Chew

, et al. Familial renal amyloidosis in Abyssinian cats. Vet Pathol. 1984;21:33–38.

21.

Buchanan

Varghese

Johnston

, et al. Functional amyloids: where supramolecular amyloid assembly controls biological activity or generates new functionality. J Mol Biol. 2023;435:167919.

22.

Bufi

Korstanje

The impact of genetic background on mouse models of kidney disease. Kidney Int. 2022;102:38–44.

23.

Burns

Gaffney

Nilsson

KPR

, et al. Systemic amyloidosis in an African tiger snake (Telescopus semiannulatus). J Comp Pathol. 2017;157:136–140.

24.

Buxbaum

Dispenzieri

Eisenberg

, et al. Amyloid nomenclature 2022: update, novel proteins, and recommendations by the International Society of Amyloidosis (ISA) Nomenclature Committee. Amyloid. 2022;29:213–219.

25.

Camus

Brown

Field

, et al. Amyloid-like renal lesions in a roughtail stingray Dasyatis centroura (Mitchill 1815). J Fish Dis. 2016;39:613–617.

26.

Carlson

Prusiner

SB.

How an infection of sheep revealed prion mechanisms in Alzheimer’s disease and other neurodegenerative disorders. Int J Mol Sci. 2021;22:4861.

27.

Castillo

Aplin

Hackney

, et al. Islet amyloid polypeptide aggregation exerts cytotoxic and proinflammatory effects on the islet vasculature in mice. Diabetologia. 2022;65:1687–1700.

28.

Cavanagh

JB.

Corpora-amylacea and the family of polyglucosan diseases. Brain Res Rev. 1999;29:265–295.

29.

Chambers

Kanda

Shirai

, et al. Senile systemic amyloidosis in an aged savannah monkey (Cercopithecus aethiops) with tenosynovial degeneration. J Vet Med Sci. 2010;72:657–659.

30.

Chambers

Mutsuga

Uchida

, et al. Characterization of AβpN3 deposition in the brains of dogs of various ages and other animal species. Amyloid. 2011;18:63–71.

31.

Chambers

Tokuda

Uchida

, et al. The domestic cat as a natural animal model of Alzheimer’s disease. Acta Neuropathol Commun. 2015;3:78.

32.

Chambers

Uchida

Harada

, et al. Neurofibrillary tangles and the deposition of a beta amyloid peptide with a novel N-terminal epitope in the brains of wild Tsushima leopard cats. PLoS ONE. 2012;7:e46452.

33.

Chambers

Uchida

Nakayama

White matter myelin loss in the brains of aged dogs. Exp Gerontol. 2012;47:263–269.

34.

Charidimou

Boulouis

Haley

, et al. White matter hyperintensity patterns in cerebral amyloid angiopathy and hypertensive arteriopathy. Neurology. 2016;86:505–511.

35.

Chen

Zhu

Wang

, et al. Amyloid A amyloidosis secondary to avian tuberculosis in naturally infected domestic Pekin ducks (Anas platyrhynchos domestica). Comp Immunol Microbiol Infect Dis. 2019;63:136–141.

36.

Cifani

Luo

, et al. Discovery of protein modifications using differential tandem mass spectrometry proteomics. J Proteome Res. 2021;20:1835–1848.

37.

Cohen

Blakeney

Law

, et al. The experience of hereditary apolipoprotein A-I amyloidosis at the UK National Amyloidosis Centre. Amyloid. 2022;29:237–244.

38.

Colussi

Vaccari

Maurella

, et al. Histidine at codon 154 of the prion protein gene is a risk factor for Nor98 scrapie in goats. J Gen Virol. 2008;89:3173–3176.

39.

Cui

Kawano

Hoshii

, et al. Acceleration of murine AA amyloid deposition by bovine amyloid fibrils and tissue homogenates. Amyloid. 2008;15:77–83.

40.

Dasari

Amin

Kurtin

, et al. Clinical, biopsy, and mass spectrometry characteristics of renal apolipoprotein A-IV amyloidosis. Kidney Int. 2016;90:658–664.

41.

Davis

Bell

Wilhelmsen

, et al. Immunohistochemical analysis of spontaneous pancreatic islet amyloid deposits in nonhuman primates. Vet Pathol. 1994;31:479–480.

42.

Dehle

Ecroyd

Musgrave

, et al. αB-crystallin inhibits the cell toxicity associated with amyloid fibril formation by κ-casein and the amyloid-β peptide. Cell Stress Chaperones. 2010;15:1013–1026.

43.

Delaney

Singh

Murphy

, et al. Immunohistochemical and biochemical evidence of ameloblastic origin of amyloid-producing odontogenic tumors in cats. Vet Pathol. 2013;50:238–242.

44.

Dittmer

Roccabianca

Bell

, et al. Surgical Pathology of Tumors of Domestic Animals (Vol. 4: Tumors of Bone, Cartilage and Other Hard Tissues). Gurnee, IL: Davis-Thompson Foundation; 2021.

45.

Edler

Sherwood

Meindl

, et al. Aged chimpanzees exhibit pathologic hallmarks of Alzheimer’s disease. Neurobiol Aging. 2017;59:107–120.

46.

Erickson

Vrana

Theis

, et al. Analysis of amyloid in medullary thyroid carcinoma by mass spectrometry-based proteomic analysis. Endocr Pathol. 2015;26:291–295.

47.

Falabella

Riviello

Pascale

, et al. Functional amyloids in insect immune response. Insect Biochem Mol Biol. 2012;42:203–211.

48.

Farrell

Cooke

Wickham

, et al. Environmental inﬂuences on bovine κ-casein: reduction and conversion to fibrillar (amyloid) structures. J Protein Chem. 2003;22:259–273.

49.

Faunt

Turk

Cohn

, et al. Isolated right-ventricular hypertrophy associated with severe pulmonary vascular apolipoprotein A1-derived amyloidosis in a dog. J Am Anim Hosp Assoc. 1998;34:35–37.

50.

Feberwee

De Vries

Landman

WJM

. Seroprevalence of Mycoplasma synoviae in Dutch commercial poultry farms. Avian Pathol. 2008;37:629–633.

51.

Ferri

Ferro

Porporato

, et al. AA-amyloidosis in cats (Felis catus) housed in shelters. PLoS ONE. 2023;18:e0281822.

52.

Fesharaki-Zadeh

Chronic traumatic encephalopathy: a brief overview. Front Neurol. 2019;10:713.

53.

Fiock

Smith

Crary

, et al. β-amyloid and tau pathology in the aging feline brain. J Comp Neurol. 2020;528:112–117.

54.

Fortin

Benoit-Biancamano

M-O.

Wildlife sequences of islet amyloid polypeptide (IAPP) identify critical species variants for fibrillization. Amyloid. 2015;22:194–202.

55.

Fortin

Hetak

Duggan

, et al. Equine pituitary pars intermedia dysfunction: a spontaneous model of synucleinopathy. Sci Rep. 2021;11:16036.

56.

Fortin

McCarty

Penticoff

, et al. Understanding alpha-synuclein aggregation propensity with a fragment peptide library. FASEB J. 2022;36:fasebj202236S10R494.

57.

Fotiadis

Reijmer

Van Veluw

, et al. White matter atrophy in cerebral amyloid angiopathy. Neurology. 2020;95:e554–e562.

58.

Frame

Kumanan

Wales

, et al. Structural basis for lipid binding and function by an evolutionarily conserved protein, serum amyloid A. J Mol Biol. 2020;432:1978–1995.

59.

Gaffney

Imai

Clifford

, et al. Proteomic analysis of highly prevalent amyloid A amyloidosis endemic to endangered island foxes. PLoS ONE. 2014;9:e113765.

60.

Gaffney

Witte

Clifford

, et al. Systemic amyloid A amyloidosis in island foxes (Urocyon littoralis): severity and risk factors. Vet Pathol. 2016;53:637–647.

61.

Gao

Liu

, et al. Imaging and spectral characteristics of amyloid plaque autofluorescence in brain slices from the APP/PS1 mouse model of Alzheimer’s disease. Neurosci Bull. 2019;35:1126–1137.

62.

Gardner

Dubielzig

McGee

EV.

The so-called calcifying epithelial odontogenic tumour in dogs and cats (amyloid-producing odontogenic tumour). J Comp Pathol. 1994;111:221–230.

63.

Garnier

Briki

Nedelec

, et al. VLITL is a major cross-β-sheet signal for fibrinogen Aα-chain frameshift variants. Blood. 2017;130:2799–2807.

64.

Garza

Monzón

Marín

, et al. Distribution of peripheral PrPSc in sheep with naturally acquired scrapie. PLoS ONE. 2014;9:e97768.

65.

Gavier-Widén

Stack

Baron

, et al. Diagnosis of transmissible spongiform encephalopathies in animals: a review. J Vet Diagn Invest. 2005;17:509–527.

66.

Gerson

Mudher

Kayed

Potential mechanisms and implications for the formation of tau oligomeric strains. Crit Rev Biochem Mol Biol. 2016;51:482–496.

67.

Gertz

MA.

Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment. Am J Hematol. 2022;97:818–829.

68.

Gilead

Wolfenson

Gazit

Molecular mapping of the recognition interface between the islet amyloid polypeptide and insulin. Angew Chem Int Ed. 2006;45:6476–6480.

69.

Gillmore

Lachmann

Rowczenio

, et al. Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen Aα-chain amyloidosis. J Am Soc Nephrol. 2009;20:444–451.

70.

Goldschmidt

Teng

Riek

, et al. Identifying the amylome, proteins capable of forming amyloid-like fibrils. Proc Natl Acad Sci. 2010;107:3487–3492.

71.

Goto

Nakajima

Yamamoto

, et al. Supersaturation, a critical factor underlying proteostasis of amyloid fibril formation. J Mol Biol. 2024;436:168475.

72.

Gottwald

Röcken

The amyloid proteome: a systematic review and proposal of a protein classification system. Crit Rev Biochem Mol Biol. 2021;56:526–542.

73.

Greenlee

JJ.

Review: update on classical and atypical scrapie in sheep and goats. Vet Pathol. 2019;56:6–16.

74.

Guiroy

Williams

Yanagihara

, et al. Topographic distribution of scrapie amyloid-immunoreactive plaques in chronic wasting disease in captive mule deer (Odocoileus hemionus hemionus). Acta Neuropathol (Berl). 1991;81:475–478.

75.

Gunn-Moore

McVee

Bradshaw

, et al. Ageing changes in cat brains demonstrated by β-amyloid and AT8-immunoreactive phosphorylated tau deposits. J Feline Med Surg. 2006;8:234–242.

76.

Guo

Mori

, et al. Amyloidosis modifier genes in the less amyloidogenic A/J mouse strain. Lab Invest. 2003;83:1605–1613.

77.

Guru KrishnaKumar

Baweja

Ralhan

, et al. Carbamylation promotes amyloidogenesis and induces structural changes in tau-core hexapeptide fibrils. Biochim Biophys Acta Gen Subj. 2018;1862:2590–2604.

78.

Hamada

Dobson

CM.

A kinetic study of β-lactoglobulin amyloid fibril formation promoted by urea. Protein Sci. 2002;11:2417–2426.

79.

Hamir

Miller

Cutlip

, et al. Transmission of sheep scrapie to elk (Cervus Elaphus Nelsoni) by intracerebral inoculation: final outcome of the experiment. J Vet Diagn Invest. 2004;16:316–321.

80.

Hanari

Nagashima

Machida

, et al. Gastric plasmacytoma with immunoglobulin lambda light chain deposition in a dog. J Comp Pathol. 2021;187:7–10.

81.

Hartig

Leifsson

Nielsen

OL.

Immunohistochemical identification of amyloid, using an anti-human serum amyloid P component (SAP) antibody, is possible in ruminants but not in dogs and cats. J Vet Med Ser A. 2005;52:447–453.

82.

Hartl

Bracher

Hayer-Hartl

Molecular chaperones in protein folding and proteostasis. Nature. 2011;475:324–332.

83.

Head

Moffat

Das

, et al. β-amyloid deposition and tau phosphorylation in clinically characterized aged cats. Neurobiol Aging. 2005;26:749–763.

84.

Hellman

Wernstedt

Westermark

, et al. Amino acid sequence from degu islet amyloid-derived insulin shows unique sequence characteristics. Biochem Biophys Res Commun. 1990;169:571–577.

85.

Higuchi

Kogishi

Wang

, et al. Fibrilization in mouse senile amyloidosis is fibril conformation-dependent. Lab Invest. 1998;78:1535–1542.

86.

Higuchi

Naiki

Kitagawa

, et al. Mouse senile amyloidosis. ASSAM amyloidosis in mice presents universally as a systemic age-associated amyloidosis. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60:231–238.

87.

Hirayama

Endoh

Kagawa

, et al. Amyloid-producing odontogenic tumors of the facial skin in three cats. Vet Pathol. 2017;54:218–221.

88.

Hirayama

Kagawa

Nihtani

, et al. Thyroid C-cell carcinoma with amyloid in a red fox (Vulpes vulpes schrenchki). Vet Pathol. 1999;36:342–344.

89.

Hirayama

Miyasho

Ohmachi

, et al. Biochemical and immunohistochemical characterization of the amyloid in canine amyloid-producing odontogenic tumor. Vet Pathol. 2010;47:915–922.

90.

Holub

Flodrova

Pika

, et al. Mass spectrometry amyloid typing is reproducible across multiple organ sites. BioMed Res Int. 2019;2019:3689091.

91.

Hoppe

Uzunoğlu

Nussbaum-Krammer

α-synuclein strains: does amyloid conformation explain the heterogeneity of synucleinopathies?

Biomolecules. 2021;11:931.

92.

Hubbard

Lee

Steele

, et al. Spontaneous amyloidosis in twelve chimpanzees, Pan troglodytes. J Med Primatol. 2001;30:260–267.

93.

Hull

Westermark

, et al. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab. 2004;89:3629–3643.

94.

Imran

Mahmood

An overview of animal prion diseases. Virol J. 2011;8:493.

95.

Inman

Allen-Durrance

Cianciolo

, et al. Familial nephropathy in Bracchi Italiani: 8 cases (2012–2019). J Am Vet Med Assoc. 2021;259:1422–1427.

96.

Inoue

Miyazaki

Kobayashi

, et al. Pathological characterization of spontaneous AA amyloidosis in microminipigs. Toxicol Pathol. 2023;51:257–263.

97.

Iwaide

Ito

Ogino

, et al. Fibrinogen Aα-chain amyloidosis outbreaks in Japanese squirrels (Sciurus lis): a potential disease model. J Pathol. 2023;261:96–104.

98.

Iwaide

Nakayama

Chambers

, et al. Senile plaques and phosphorylated tau deposition in a super-aged rhesus monkey (Macaca mulatta). J Vet Med Sci. 2023;85:1296–1300.

99.

Iwaide

Oba

Kobayashi

, et al. Local administration of amyloid enhancing factor initiates in situ amyloid A deposition followed by systemic lesions in mice. Exp Anim. 2023;72:218–223.

100.

Iwaide

Yanai

Murakami

Proteopathic lesions in the brain of a super-aged chimpanzee (Pan troglodytes). J Med Primatol. 2021;50:222–224.

101.

Izzati

Hidaka

Hirai

, et al. Immunohistochemical profile of ameloblastic carcinoma arising from an amyloid-producing odontogenic tumour in a miniature dachshund. J Comp Pathol. 2019;166:54–58.

102.

Jacobson

Pastore

Yaghoubian

, et al. Variant-sequence transthyretin (Isoleucine 122) in late-onset cardiac amyloidosis in black Americans. N Engl J Med. 1997;336:466–473.

103.

Jakob

Spontaneous amyloidosis of mammals. Vet Pathol. 1971;8:292–306.

104.

Janke

Beck

Stahl

, et al. Phylogenetic diversity of the expression of the microtubule-associated protein tau: implications for neurodegenerative disorders. Mol Brain Res. 1999;68:119–128.

105.

Jernvall

Thesleff

Tooth shape formation and tooth renewal: evolving with the same signals. Development. 2012;139:3487–3497.

106.

Johnson

Pedersen

Chappell

, et al. Oral transmissibility of prion disease is enhanced by binding to soil particles. PLoS Pathog. 2007;3:e93.

107.

Johnson

Phillips

Schramm

, et al. Prions adhere to soil minerals and remain infectious. PLoS Pathog. 2006;2:e32.

108.

Johnson

Sletten

O’Brien

, et al. Pulmonary vascular amyloidosis in aged dogs. Am J Pathol. 1992;141:1013–1019.

109.

Johnson

Wernsted

O’Brien

, et al. Amyloid in the pancreatic islets of the cougar (Felis concolor) is derived from islet amyloid polypeptide (IAPP). Comp Biochem Physiol Part B Comp Biochem. 1991;98:115–119.

110.

Jotha-Mattos

Vieira

Castelo

MDSM

, et al. Amyloidogenesis of feline amylin and plasma levels in cats with diabetes mellitus or pancreatitis. Domest Anim Endocrinol. 2021;74:106532.

111.

Kadota

Iwaide

Miyazaki

, et al. Pathology and proteomics-based diagnosis of localized light-chain amyloidosis in dogs and cats. Vet Pathol. 2020;57:658–665.

112.

Kamiie

Sugahara

Yoshimoto

, et al. Identification of a unique amyloid sequence in AA amyloidosis of a pig associated with Streptococcus suis infection. Vet Pathol. 2017;54:111–118.

113.

Kanenawa

Ueda

Isoguchi

, et al. Histopathological and biochemical analyses of prostate corpora amylacea. Amyloid. 2019;26:160–161.

114.

Kang

M-S

Park

M-S

Kwon

S-W

, et al. Amyloid-producing odontogenic tumour (calcifying epithelial odontogenic tumour) in the mandible of a Bengal tiger (Panthera tigris tigris). J Comp Pathol. 2006;134:236–240.

115.

Kanou

Fukui

Yamamoto

, et al. Gastroinvasive Helicobacter infection in an ocelot (Leopardus pardalis). J Comp Pathol. 2005;133:281–285.

116.

Kershaw

Linek

Linke

, et al. Intraocular ALλ amyloidoma with plasma cell neoplasia in a cat. Vet Ophthalmol. 2011;14:88–92.

117.

Kiatipattanasakul

Nakayama

Yongsiri

, et al. Abnormal neuronal and glial argyrophilic fibrillary structures in the brain of an aged albino cynomolgus monkey (Macaca fascicularis). Acta Neuropathol (Berl). 2000;100:580–586.

118.

Kim

Taylor

Eades

, et al. Systemic AL amyloidosis associated with multiple myeloma in a horse. Vet Pathol. 2005;42:81–84.

119.

Kitagawa

Wang

Mastushita

, et al. Polymorphisms of mouse apolipoprotein A-11: seven alleles found among 41 inbred strains of mice. Amyloid. 2003;10:207–214.

120.

Kittelberger

Chaplin

Simmons

, et al. Atypical scrapie/Nor98 in a sheep from New Zealand. J Vet Diagn Invest. 2010;22:863–875.

121.

Klein

Radespiel

Felmy

, et al. AA-amyloidosis in captive northern tree shrews (Tupaia belangeri). Vet Pathol. 2022;59:340–347.

122.

Kluve-Beckerman

Smith

Ivancic

, et al. Post-translational modification of amyloid a protein in patients with AA amyloidosis. Amyloid. 2022;29:50–57.

123.

Knowles

Fitzpatrick

Meehan

, et al. Role of intermolecular forces in defining material properties of protein nanofibrils. Science. 2007;318:1900–1903.

124.

Kobayashi

Iwaide

Sakai

, et al. Keratinic amyloid deposition in canine hair follicle tumors. Vet Pathol. 2023;60:60–68.

125.

Kobayashi

Iwaide

Fukui

, et al. Apolipoprotein C-III amyloidosis in white lions (Panthera leo). Vet Pathol. 2024;61:574–581.

126.

Kobayashi

Murakami

Sakai

, et al. Chicken amyloid arthropathy caused by Mycoplasma synoviae infection in Japan. J Vet Sci Med Diagn. 2016;5:6.

127.

Koch

KM.

Dialysis-related amyloidosis. Kidney Int. 1992;41:1416–1429.

128.

Kok

Chambers

Ushio

, et al. Amyloid-producing odontoameloblastoma in a black-tailed prairie dog (Cynomys ludovicianus). J Comp Pathol. 2018;159:26–30.

129.

Korenaga

Yan

Sawashita

, et al. Transmission of amyloidosis in offspring of mice with AApoAII Amyloidosis. Am J Pathol. 2006;168:898–906.

130.

Kyle

RA.

Amyloidosis: a convoluted story: historical review. Br J Haematol. 2001;114:529–538.

131.

Lam

Petit

Hérard

A-S

, et al. Transmission of amyloid-beta and tau pathologies is associated with cognitive impairments in a primate. Acta Neuropathol Commun. 2021;9:165.

132.

Landman

WJM.

Amyloid arthropathy in chickens: (summary of thesis, Utrecht University, faculty of veterinary medicine, 1998). Vet Q. 1999;21:78–82.

133.

Landman

WJM

Gruys

Dwars

. A syndrome associated with growth depression and amyloid arthropathy in layers: a preliminary report. Avian Pathol. 1994;23:461–470.

134.

Landman

WJM

Sletten

Koch

CAM

, et al. Chicken joint amyloid protein is of the AA-type. I. Characterization of the amyloid protein. Scand J Immunol. 1996;43:210–218.

135.

Dai

Kametani

, et al. Renal function in aged C57BL/6J mice is impaired by deposition of age-related apolipoprotein A-II amyloid independent of kidney aging. Am J Pathol. 2023;193:725–739.

136.

Liberta

Loerch

Rennegarbe

, et al. Cryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids. Nat Commun. 2019;10:1104.

137.

Lin

Kuragano

Watanabe

, et al. Comparison of AA amyloid fibril morphology and serum amyloid A gene sequence in 5 animal species. Vet Pathol. 2021;58:369–375.

138.

Linke

Geisel

Mann

Equine cutaneous amyloidosis derived from an immunoglobulin lambda-light chain. Immunohistochemical, immunochemical and chemical results. Biol Chem Hoppe Seyler. 1991;372:835–843.

139.

Liu

Guo

J-J

J-H

, et al. Differential seeding and propagating efficiency of α-synuclein strains generated in different conditions. Transl Neurodegener. 2021;10:20.

140.

Löhr

CV.

One hundred two tumors in 100 goats (1987–2011). Vet Pathol. 2013;50:668–675.

141.

Loo

Mollee

Renaut

, et al. Proteomics in molecular diagnosis: typing of amyloidosis. J Biomed Biotechnol. 2011;754109:1–9.

142.

Ludlage

Murphy

Davern

, et al. Systemic AA amyloidosis in the common marmoset. Vet Pathol. 2005;42:117–124.

143.

Lundmark

Westermark

Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc Natl Acad Sci. 2002;100:6979–6984.

144.

Manganelli

Fabrizi

Luigetti

, et al. Hereditary transthyretin amyloidosis overview. Neurol Sci. 2022;43:595–604.

145.

Manka

Wenborn

Betts

, et al. A structural basis for prion strain diversity. Nat Chem Biol. 2023;19:607–613.

146.

Martínez

Lichtman

EI.

Localized light chain amyloidosis: a self-limited plasmacytic B-cell lymphoproliferative disorder. Front Oncol. 2022;12:1002253.

147.

Martins

Urbano

Leite

, et al. Cardiac amyloidosis associated with apolipoprotein A-IV deposition diagnosed by mass spectrometry-based proteomic analysis. Eur J Case Rep Intern Med. 2019;29:222–225.

148.

Masoud

Iwaide

Itoh

, et al. Identification of ameloblastin as an amyloid precursor protein of amyloid-producing ameloblastoma in dogs and cats. Vet Sci. 2023;10:166.

149.

Masuda-Suzukake

Nonaka

Hosokawa

, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136:1128–1138.

150.

Matsuura

Miyazawa

Imamura

, et al. First case of atypical scrapie in a goat in Japan. J Vet Med Sci. 2019;81:986–989.

151.

McFarlane

Dybdal

Donaldson

, et al. Nitration and increased α-synuclein expression associated with dopaminergic neurodegeneration in equine pituitary pars intermedia dysfunction. J Neuroendocrinol. 2005;17:73–80.

152.

McKee

Stein

Nowinski

, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013;136:43–64.

153.

Meek

Benditt

EP.

Rat tissues express serum amyloid A protein-related mRNAs. Proc Natl Acad Sci. 1989;86:1890–1894.

154.

Mehra

Sahay

Maji

SK.

α-Synuclein misfolding and aggregation: implications in Parkinson’s disease pathogenesis. Biochim Biophys Acta BBA—Proteins Proteomics. 2019;1867:890–908.

155.

Ménsua

Carrasco

Bautista

, et al. Pathology of AA amyloidosis in domestic sheep and goats. Vet Pathol. 2003;40:71–80.

156.

Mereuta

Dogan

Cutaneous amyloidosis. In: Picken

Herrera

Dogan

, eds. Amyloid and Related Disorders. Springer International Publishing 2015:469–479.

157.

Miller

MET

M-H

Baghai

, et al. Analysis of sheep and goat IAPP provides insight into IAPP amyloidogenicity and cytotoxicity. Biochemistry. 2022;61:2531–2545.

158.

Mitchell

O’Rourke

Harrington

, et al. Identification of atypical scrapie in Canadian sheep. J Vet Diagn Invest. 2010;22:408–411.

159.

Miyahara

Sawashita

Ishikawa

, et al. Comprehensive proteomic profiles of mouse AApoAII amyloid fibrils provide insights into the involvement of lipoproteins in the pathology of amyloidosis. J Proteomics. 2018;172:111–121.

160.

Miyazaki

Kadota

Mitsui

, et al. Amyloid signature proteins in feline amyloidosis. J Comp Pathol. 2020;177:10–17.

161.

Miyazaki

Kobayashi

Kametani

, et al. Systemic amyloidosis derived from EFEMP1 in a captive Tsushima leopard cat. Vet Pathol. 2022;59:152–156.

162.

Miyoshi

Ono

Shimada

, et al. Experimental model of oral transmissible AA amyloidosis in quails. Avian Pathol. 2019;48:521–527.

163.

Morotomi

Kawano

Toyono

, et al. In vitro differentiation of dental epithelial progenitor cells through epithelial–mesenchymal interactions. Arch Oral Biol. 2005;50:695–705.

164.

Mucchiano

Häggqvist

Sletten

, et al. Apolipoprotein A-1-derived amyloid in atherosclerotic plaques of the human aorta. J Pathol. 2001;193:270–275.

165.

Murakami

Inoshima

Kobayashi

, et al. Atypical AA amyloid deposits in bovine AA amyloidosis. Amyloid. 2012;19:15–20.

166.

Murakami

Inoshima

Sakamoto

, et al. AA amyloidosis in vaccinated growing chickens. J Comp Pathol. 2013;149:291–297.

167.

Murakami

Inoshima

Watanabe

K-I

, et al. Pathogenesis of experimental amyloid protein A amyloidosis in sore hocks-affected rabbits. Amyloid. 2011;18:112–118.

168.

Murakami

Ishiguro

Higuchi

Transmission of systemic AA amyloidosis in animals. Vet Pathol. 2014;51:363–371.

169.

Murakami

Kaku

Tsukakoshi

, et al. Identification of novel amyloidosis in dogs: α-S1-casein acquires amyloidogenicity in mammary tumor by overexpression and N-terminal truncation. Vet Pathol. 2023;60:203–213.

170.

Murakami

Kobayashi

Iwaide

, et al. Identification of calcitonin receptor-stimulating peptide 1-derived amyloid in a feline C-cell carcinoma. Amyloid. 2024;31:142–144.

171.

Murakami

Muhammad

Inoshima

, et al. Experimental induction and oral transmission of avian AA amyloidosis in vaccinated white hens. Amyloid. 2013;20:80–85.

172.

Murakami

Noguchi

Hachiya

, et al. Needle-shaped amyloid deposition in rat mammary gland: evidence of a novel amyloid fibril protein. Amyloid. 2020;27:25–35.

173.

Murakami

Takasawa

Moriki

, et al. A systemic apolipoprotein A-IV-associated amyloidosis confirmed by proteome analysis. Virchows Arch. 2021;479:1041–1046.

174.

Naiki

Okoshi

Ozawa

, et al. Molecular pathogenesis of human amyloidosis: lessons from β 2-microglobulin-related amyloidosis. Pathol Int. 2016;66:193–201.

175.

Nakagun

Watanabe

Tajima

, et al. Systemic amyloid A amyloidosis in Stejneger’s beaked whales (Mesoplodon stejnegeri). Vet Pathol. 2020;57:437–444.

176.

Nakamura

Okabayashi

Ageyama

, et al. Transthyretin amyloidosis and two other aging-related amyloidoses in an aged vervet monkey. Vet Pathol. 2008;45:67–72.

177.

Nakano

Madarame

Systemic amyloid A (AA) amyloidosis in the Bengalese finch (Lonchura striata var. domestica). J Vet Med Sci. 2020;82:1484–1487.

178.

Nakayama

Kamiie

Watanabe

, et al. Spontaneous, experimentally induced, and transmissible AA amyloidosis in Japanese quail (Coturnix japonica). Vet Pathol. 2017;54:912–921.

179.

Nicot

Verchère

Bélondrade

, et al. Seeded propagation of α-synuclein aggregation in mouse brain using protein misfolding cyclic amplification. FASEB J. 2019;33:12073–12086.

180.

Niewold

Murphy

Hulskamp-Koch

CAM

, et al. Casein related amyloid, characterization of a new and unique amyloid protein isolated from bovine corpora amylacea. Amyloid. 1999;6:244–249.

181.

Novakofski

Brewer

Mateus-Pinilla

, et al. Prion biology relevant to bovine spongiform encephalopathy. J Anim Sci. 2005;83:1455–1476.

182.

Oba

Ujike

Ono

, et al. Label-free autofluorescence and hyperspectral imaging of cerebral amyloid-β lesions in aged squirrel monkeys. J Vet Diagn Invest. 2024;36:41–45.

183.

O’Brien

TD.

Pathogenesis of feline diabetes mellitus. Mol Cell Endocrinol. 2002;197:213–219.

184.

O’Brien

Hayden

O’Leary

, et al. Canine pancreatic endocrine tumors: immunohistochemical analysis of hormone content and amyloid. Vet Pathol. 1987;24:308–314.

185.

O’Brien

Westermark

Johnson

KH.

Islet amyloid polypeptide and calcitonin gene-related peptide immunoreactivity in amyloid and tumor cells of canine pancreatic endocrine tumors. Vet Pathol. 1990;27:194–198.

186.

Ohmachi

Taniyama

Nakade

, et al. Calcifying epithelial odontogenic tumours in small domesticated carnivores: histological, immunohistochemical and electron microscopical studies. J Comp Pathol. 1996;114:305–314.

187.

Okada

Miyazawa

Fukuda

, et al. The presence of disease-associated prion protein in skeletal muscle of cattle infected with classical bovine spongiform encephalopathy. J Vet Med Sci. 2014;76:103–107.

188.

Omoto

Yokota

Cui

, et al. Inactivation of amyloid-enhancing factor (AEF): study on experimental murine AA amyloidosis. Med Mol Morphol. 2007;40:88–94.

189.

Ono

Nakayama

Inoue

, et al. AA amyloid deposition in the central and peripheral nervous systems in flamingos. Vet Pathol. 2020;57:700–705.

190.

Orge

Lima

Machado

, et al. Neuropathology of animal prion diseases. Biomolecules. 2021;11:466.

191.

Oueslati

Ximerakis

Vekrellis

Protein transmission, seeding and degradation: key steps for α-synuclein prion-like propagation. Exp Neurobiol. 2014;23:324–336.

192.

Ozawa

Chambers

Uchida

, et al. The relation between canine cognitive dysfunction and age-related brain lesions. J Vet Med Sci. 2016;78:997–1006.

193.

Palstrøm

Rojek

Møller

HEH

, et al. Classification of amyloidosis by model-assisted mass spectrometry-based proteomics. Int J Mol Sci. 2021;23:319.

194.

Pan

Zhong

Amyloid-like fibrils formed from intrinsically disordered caseins: physicochemical and nanomechanical properties. Soft Matter. 2015;11:5898–5904.

195.

Papendick

Munson

O’Brien

, et al. Systemic AA Amyloidosis in captive cheetahs (Acinonyx jubatus). Vet Pathol. 1997;34:549–556.

196.

Patnaik

Lieberman

PH.

Gross, histologic, cytochemical, and immunocytochemical study of medullary thyroid carcinoma in sixteen dogs. Vet Pathol. 1991;28:223–233.

197.

Patnaik

Lieberman

Erlandson

, et al. Canine medullary carcinoma of the thyroid. Vet Pathol. 1978;15:590–599.

198.

Perez

Sherwood

Cranfield

, et al. Early Alzheimer’s disease–type pathology in the frontal cortex of wild mountain gorillas (Gorilla beringei beringei). Neurobiol Aging. 2016;39:195–201.

199.

Polverino

Laureto

Frare

Battaglia

, et al. Protein dissection enhances the amyloidogenic properties of α-lactalbumin: proteolysis of proteins enhances fibrillogenesis. FEBS J. 2005;272:2176–2188.

200.

Radamaker

Lin

Y-H

Annamalai

, et al. Cryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis. Nat Commun. 2019;10:1103.

201.

Ramesh

Gopinath

Govindaraju

Role of post-translational modifications in Alzheimer’s disease. ChemBioChem. 2020;21:1052–1079.

202.

Ramms

Gordts

PLSM

. Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism. Curr Opin Lipidol. 2018;29:171–179.

203.

Ramos-Vara

JA.

Technical aspects of immunohistochemistry. Vet Pathol. 2005;42:405–426.

204.

Ramos-Vara

Miller

Pace

, et al. Intestinal multinodular Aλ-amyloid deposition associated with extramedullary plasmacytoma in three dogs: clinicopathological and immunohistochemical studies. J Comp Pathol. 1998;119:239–249.

205.

Rand

JS.

Pathogenesis of feline diabetes. Vet Clin North Am Small Anim Pract. 2013;43:221–231.

206.

Recasens

Dehay

Bové

, et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys: LB-induced pathology. Ann Neurol. 2014;75:351–362.

207.

Renzoni

Taccini

Lossi

, et al. Thyroid C-cells carcinoma in a sheep: histopathological and immunocytochemical study. Vet Pathol. 1995;32:727–730.

208.

Riba

Augé

Campo-Sabariz

, et al. Corpora amylacea act as containers that remove waste products from the brain. Proc Natl Acad Sci. 2019;116:26038–26048.

209.

Riba

Del Valle

Augé

, et al. From corpora amylacea to wasteosomes: history and perspectives. Ageing Res Rev. 2021;72:101484.

210.

Riba

Del Valle

Molina-Porcel

, et al. Wasteosomes (corpora amylacea) as a hallmark of chronic glymphatic insufficiency. Proc Natl Acad Sci. 2022;119:e2211326119.

211.

Rising

Cederlund

Palmberg

, et al. Systemic AA amyloidosis in the red fox (Vulpes vulpes). Protein Sci. 2017;26:2312–2318.

212.

Rochet

J-C

Lansbury

PT.

Amyloid fibrillogenesis: themes and variations. Curr Opin Struct Biol. 2000;10:60–68.

213.

Röcken

Linke

Saeger

Corpora amylacea in the lung, prostate and uterus. Pathol—Res Pract. 1996;192:998–1006.

214.

Röcken

Shakespeare

Pathology, diagnosis and pathogenesis of AA amyloidosis. Virchows Arch. 2002;440:111–122.

215.

Roertgen

Lund

O’Brien

, et al. Apolipoprotein AI-derived pulmonary vascular amyloid in aged dogs. Am J Pathol. 1995;147:1311–1317.

216.

Röhr

Boon

BDC

Schuler

, et al. Label-free vibrational imaging of different Aβ plaque types in Alzheimer’s disease reveals sequential events in plaque development. Acta Neuropathol Commun. 2020;8:222.

217.

Rosen

Farberg

Gearing

, et al. Tauopathy with paired helical filaments in an aged chimpanzee. J Comp Neurol. 2008;509:259–270.

218.

Rosenblum

WI.

The presence, origin, and significance of Aβ peptide in the cell bodies of neurons. J Neuropathol Exp Neurol. 1999;58:575–581.

219.

Rowland

Linke

RP.

Immunohistochemical characterization of lambda light-chain-derived amyloid in one feline and five canine plasma cell tumors. Vet Pathol. 1994;31:390–393.

220.

Sahin

Kjær

Christensen

, et al. α-synucleins from animal species show low fibrillation propensities and weak oligomer membrane disruption. Biochemistry. 2018;57:5145–5158.

221.

Sawashita

Zhang

Hasegawa

, et al. C-terminal sequence of amyloid-resistant type F apolipoprotein A-II inhibits amyloid fibril formation of apolipoprotein A-II in mice. Proc Natl Acad Sci. 2015;112:E836–E845.

222.

Schmitt

Jacobi

Susnik

, et al. Ageing mouse kidney—not always the SAME old story. Nephrol Dial Transplant. 2009;24:3002–3005.

223.

Schulze

Brügmann

Böer

, et al. Generalized AA-amyloidosis in Siberian tigers (Panthera tigris altaica) with predominant renal medullary amyloid deposition. Vet Pathol. 1998;35:70–74.

224.

Sedghi Masoud

Iwaide

Itoh

, et al. Apolipoprotein A-IV amyloidosis in a cotton-top tamarin (Saguinus oedipus). Amyloid. 2023;3:348–350.

225.

Segev

Cowgill

Jessen

, et al. Renal amyloidosis in dogs: a retrospective study of 91 cases with comparison of the disease between Shar-Pei and non-Shar-Pei Dogs. J Vet Intern Med. 2012;26:259–268.

226.

Serizawa

Chambers

Une

Beta amyloid deposition and neurofibrillary tangles spontaneously occur in the brains of captive cheetahs (Acinonyx jubatus). Vet Pathol. 2012;49:304–312.

227.

Sigurdson

Miller

MW.

Other animal prion diseases. Br Med Bull. 2003;66:199–212.

228.

Sigurdson

Williams

Miller

, et al. Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). J Gen Virol. 1999;80:2757–2764.

229.

Sikora

Kmochová

Mušálková

, et al. A mutation in the SAA1 promoter causes hereditary amyloid A amyloidosis. Kidney Int. 2022;101:349–359.

230.

Sipe

Benson

Buxbaum

, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23: 209–213.

231.

Solomon

Richey

Murphy

, et al. Amyloidogenic potential of foie gras. Proc Natl Acad Sci. 2007;104:10998–11001.

232.

Sordo

Martini

Houston

, et al. Neuropathology of aging in cats and its similarities to human Alzheimer’s disease. Front Aging. 2021;2:684607.

233.

Spear

Caple

Sutherland

LR.

The pancreas in the degu. Exp Mol Pathol. 1984;40:295–310.

234.

Spraker

Zink

Cummings

, et al. Comparison of histological lesions and immunohistochemical staining of proteinase-resistant prion protein in a naturally occurring spongiform encephalopathy of free-ranging mule deer (Odocoileus hemionus) with those of chronic wasting disease of captive mule deer. Vet Pathol. 2002;39:110–119.

235.

Steentjes

Veldman

Mevius

, et al. Molecular epidemiology of unilateral amyloid arthropathy in broiler breeders associated with Enterococcus faecalis. Avian Pathol. 2002;31:31–39.

236.

Stefani

Dobson

CM.

Protein aggregation and aggregate toxicity: new insights into protein folding, misfolding diseases and biological evolution. J Mol Med. 2003;81:678–699.

237.

Strörkel

Schneider

Müntefering

, et al. Iatrogenic, insulin-dependent, local amyloidosis. Lab Invest. 1983;48:108–111.

238.

Sulzer

Edwards

The physiological role of α-synuclein and its relationship to Parkinson’s disease. J Neurochem. 2019;150:475–486.

239.

Swuec

Lavatelli

Tasaki

, et al. Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient. Nat Commun. 2019;10:1269.

240.

Sykes

Byfield

Sullivan

, et al. Feline respiratory extramedullary plasmacytoma with lymph node metastasis and intrahistiocytic amyloid. J Comp Pathol. 2017;156:173–177.

241.

Symmers WSC. Primary amyloidosis: a review. J Clin Pathol. 1956;9:187–211.

242.

Taira

Inoshima

Ishiguro

, et al. Isolation and characterization of monoclonal antibodies against bovine serum amyloid A1 protein. Amyloid. 2009;16:215–220.

243.

Takahashi

Chambers

Takaichi

, et al. Different Aβ43 deposition patterns in the brains of aged dogs, sea lions, and cats. J Vet Med Sci. 2022;84:1563–1573.

244.

Takaichi

Chambers

Ano

, et al. Deposition of phosphorylated α-synuclein and activation of GSK-3β and PP2A in the PS19 mouse model of tauopathy. J Neuropathol Exp Neurol. 2021;80:731–740.

245.

Takaichi

Chambers

Inoue

, et al. Phosphorylation and oligomerization of α-synuclein associated with GSK-3β activation in the rTg4510 mouse model of tauopathy. Acta Neuropathol Commun. 2020;8:86.

246.

Takaichi

Chambers

Takahashi

, et al. Amyloid β and tau pathology in brains of aged pinniped species (sea lion, seal, and walrus). Acta Neuropathol Commun. 2021;9:10.

247.

Takakura

Miyazawa

Kanaya

, et al. Orally administered prion protein is incorporated by M cells and spreads into lymphoid tissues with macrophages in prion protein knockout mice. Am J Pathol. 2011;179:1301–1309.

248.

Takuma

Arawaka

Mori

Isoforms changes of tau protein during development in various species. Dev Brain Res. 2003;142:121–127.

249.

Tamura

Chambers

Neo

, et al. Primary duodenal plasmacytoma with associated primary (amyloid light-chain) amyloidosis in a cat. J Feline Med Surg Open Rep. 2020;6:205511692095719.

250.

Taniyama

Kitamura

Kagawa

, et al. Localized amyloidosis in canine mammary tumors. Vet Pathol. 2000;37:104–107.

251.

Taniyama

Yamamoto

Sako

, et al. Systemic κAL amyloidosis associated with bovine leukocyte adhesion deficiency. Vet Pathol. 2000;37:98–100.

252.

Tarutani

Adachi

Akatsu

, et al. Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43. Acta Neuropathol (Berl). 2022;143:613–640.

253.

Tasaki

Lavatelli

Obici

, et al. Age-related amyloidosis outside the brain: a state-of-the-art review. Ageing Res Rev. 2021;70:101388.

254.

Tasaki

Ueda

Hoshii

, et al. A novel age-related venous amyloidosis derived from EGF-containing fibulin-like extracellular matrix protein 1. J Pathol. 2019;247:444–455.

255.

Tei

Uchida

Chambers

, et al. Mammary lipid-rich carcinoma with extensive amyloid deposition in a dog. J Vet Med Sci. 2012;74:809–811.

256.

Thorn

Meehan

Sunde

, et al. Amyloid fibril formation by bovine milk κ—casein and its inhibition by the molecular chaperones α S—and β-casein. Biochemistry. 2005;44:17027–17036.

257.

Uchida

Miyauchi

Nakayama

, et al. Amyloid angiopathy with cerebral hemorrhage and senile plaque in aged dogs. Jpn J Vet Sci. 1990;52:605–611.

258.

Uchihara

Endo

Kondo

, et al. Tau pathology in aged cynomolgus monkeys is progressive supranuclear palsy/corticobasal degeneration- but not Alzheimer disease-like -ultrastructural mapping of tau by EDX-. Acta Neuropathol Commun. 2016;4:118.

259.

Ueda

Ageyama

Nakamura

, et al. Aged vervet monkeys developing transthyretin amyloidosis with the human disease-causing Ile122 allele: a valid pathological model of the human disease. Lab Invest. 2012;92:474–484.

260.

Upragarin

Asten

Tooten

, et al. Serum amyloid A production by chicken fibroblast-like synoviocytes. Vet Immunol Immunopathol. 2005;106:39–51.

261.

Valleix

Verona

Jourde-Chiche

, et al. D25V apolipoprotein C-III variant causes dominant hereditary systemic amyloidosis and confers cardiovascular protective lipoprotein profile. Nat Commun. 2016;7:10353.

262.

Van Der Linde-Sipman

Niewold

Tooten

PCJ

, et al. Generalized AA-amyloidosis in Siamese and Oriental cats. Vet Immunol Immunopathol. 1997;56:1–10.

263.

Van Keulen

LJM

Schreuder

BEC

Meloen

, et al. Immumohistochemical detection and localization of prion protein in brain tissue of sheep with natural scrapie. Vet Pathol. 1995;32:299–308.

264.

Vos

Gruys

Amyloid in canine mammary tumors. Vet Pathol. 1985;22:347–354.

265.

Walsh

Seno

Tosatto

SCE

, et al. PASTA 2.0: an improved server for protein aggregation prediction. Nucleic Acids Res. 2014;42:W301–W307.

266.

Wang

SS-S

Good

Rymer

. The influence of phospholipid membranes on bovine calcitonin secondary structure and amyloid formation. Protein Sci. 2005;14:1419–1428.

267.

Watanabe

Uchida

Chambers

, et al. Experimental transmission of AA amyloidosis by injecting the AA amyloid protein into interleukin-1 receptor antagonist knockout (IL-1raKO) mice. Vet Pathol. 2015;52:505–512.

268.

Watts

Stöhr

Bhardwaj

, et al. Protease-resistant prions selectively decrease Shadoo protein. PLoS Pathog. 2011;7:e1002382.

269.

Westermark

Fändrich

Westermark

AA amyloidosis: pathogenesis and targeted therapy. Annu Rev Pathol Mech Dis. 2015;10:321–344.

270.

Westermark

. Localized AL amyloidosis: a suicidal neoplasm? Ups J Med Sci. 2012;117:244–250.

271.

Westermark

Andersson

Westermark

GT.

Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011;91:795–826.

272.

Westermark

Wilander

Islet amyloid in type 2 (non-insulin-dependent) diabetes is related to insulin. Diabetologia. 1983;24:342–346.

273.

Williams

ES.

Chronic wasting disease. Vet Pathol. 2005;42:530–549.

274.

Woldemeskel

A concise review of amyloidosis in animals. Vet Med Int. 2012;2012:1–11.

275.

Woodford

Tso

MO.

An ultrastructural study of the corpora amylacea of the optic nerve head and retina. Am J Ophthalmol. 1980;90:492–502.

276.

Xing

Nakamura

Chiba

, et al. Transmission of mouse senile amyloidosis. Lab Invest. 2001;81:493–499.

277.

Yakupova

Bobyleva

Vikhlyantsev

, et al. Congo red and amyloids: history and relationship. Biosci Rep. 2019;39:BSR20181415.

278.

Yamada

Kotani

Nakamura

, et al. Immunohistochemical distribution of amyloid deposits in 25 cows diagnosed with systemic AA amyloidosis. J Vet Med Sci. 2006;68:725–729.

279.

Yazaki

Yoshinaga

Sekijima

, et al. Hereditary fibrinogen Aα-chain amyloidosis in Asia: clinical and molecular characteristics. Int J Mol Sci. 2018;19:320.

280.

Yoshikawa

Matsuura

Tsuchiya

, et al. Pancreatic endocrine carcinoma with multiple hormone production in a raccoon (Procyon lotor). J Comp Pathol. 1999;120:301–306.

281.

Yoshino

Uchida

Tateyama

, et al. A retrospective study of canine senile plaques and cerebral amyloid angiopathy. Vet Pathol. 1996;33:230–234.

282.

Youssef

Capucchio

Rofina

, et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet Pathol. 2016;53:327–348.

283.

Zhang

Une

, et al. Fecal transmission of AA amyloidosis in the cheetah contributes to high incidence of disease. Proc Natl Acad Sci. 2008;105:7263–7268.

284.

Ziaunys

Sneideris

Smirnovas

Formation of distinct prion protein amyloid fibrils under identical experimental conditions. Sci Rep. 2020;10:4572.

285.

Zini

Lunardi

Zanetti

, et al. Endocrine pancreas in cats with diabetes mellitus. Vet Pathol. 2016;53:136–144.

Classification of amyloidosis and protein misfolding disorders in animals 2024: A review on pathology and diagnosis

Abstract

Keywords

Terminology

Amyloid

Amyloidosis

Amyloid Signature Protein

Amyloid Formation

Diagnostic Methods for Amyloidosis

Histologic Diagnosis

Transmission Electron Microscopy

Immunohistochemistry

Mass Spectrometry

Classification of Amyloidosis

Serum AA

Immunoglobulin Light Chain

Transthyretin

Apolipoprotein A-II

Apolipoprotein A-IV

Apolipoprotein C-III

EGF-Containing Fibulin-Like Extracellular Matrix Protein 1

Fibrinogen Aα-Chain

Apolipoprotein A-I

Islet Amyloid Polypeptide

Insulin

Amyloid β

Tau

α-Synuclein

Prion Protein

Tumor-Associated Localized Amyloidosis

Plasmacytoma

Amyloid-Producing Ameloblastoma

C-Cell Carcinoma

Mammary Gland Tumors

Amyloid Deposition of Unknown Pathological Significance

Keratinic Amyloid Deposition in the Skin

Amyloid Deposition in the Corpora Amylacea in Mammary Glands

Amyloidosis in Vertebrates Other Than Mammalian and Avian Species

Conclusion and Perspectives

Footnotes

Acknowledgements

Declaration of Conflicting Interests

Funding

ORCID iDs

References