Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD.
Discussion:
ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features.
Conclusion:
Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.
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References
1.
2021 Alzheimer's disease facts and figures. Alzheimers Dement. 2021; 17:327–406.
HardyJ, SelkoeDJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002; 297:353–356.
4.
JackCR Jr, BennettDA, BlennowK, et al.NIA-AA Research Framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14:535–562.
BraakH, AlafuzoffI, ArzbergerT, et al.Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006; 112:389–404.
8.
KinneyJW, BemillerSM, MurtishawAS, et al.Inflammation as a central mechanism in Alzheimer's disease. Alzheimers Dement (N Y). 2018; 4:575–590.
9.
CherryJD, OlschowkaJA, O'BanionMK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014; 11:98.
10.
EscartinC, GaleaE, LakatosA, et al.Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021; 24:312–325.
11.
BellaverB, Ferrari-SouzaJP, Uglione da RosL, et al. Astrocyte biomarkers in Alzheimer disease: a systematic review and meta-analysis. Neurology. 2021;96(24).
12.
HampelH, CummingsJ, BlennowK, et al.Developing the ATX(N) classification for use across the Alzheimer disease continuum. Nat Rev Neurol. 2021; 17:580–589.
13.
AsoE, FerrerI. Cannabinoids for treatment of Alzheimer's disease: moving toward the clinic. Front Pharmacol. 2014; 5:37.
14.
MackieK. Distribution of cannabinoid receptors in the central and peripheral nervous system. Handb Exp Pharmacol. 2005:299–325.
15.
HerkenhamM, LynnAB, JohnsonMR, et al.Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci. 1991; 11:563–583.
16.
KendallDA, YudowskiGA. Cannabinoid receptors in the central nervous system: their signaling and roles in disease. Front Cell Neurosci. 2017; 10:294.
17.
NyiriG, CserepC, SzabaditsE, et al.CB1 cannabinoid receptors are enriched in the perisynaptic annulus and on preterminal segments of hippocampal GABAergic axons. Neuroscience. 2005; 136:811–822.
18.
ShenM, PiserTM, SeyboldVS, et al.Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci. 1996; 16:4322–4334.
19.
GiffordAN, SamiianL, GatleySJ, et al.Examination of the effect of the cannabinoid receptor agonist, CP 55,940, on electrically evoked transmitter release from rat brain slices. Eur J Pharmacol. 1997; 324:187–192.
20.
SchlickerE, TimmJ, ZentnerJ, et al.Cannabinoid CB1 receptor-mediated inhibition of noradrenaline release in the human and guinea-pig hippocampus. Naunyn Schmiedebergs Arch Pharmacol. 1997; 356:583–589.
21.
HanJ, KesnerP, Metna-LaurentM, et al.Acute cannabinoids impair working memory through astroglial CB1 receptor modulation of hippocampal LTD. Cell. 2012; 148:1039–1050.
22.
Molina-HolgadoE, VelaJM, Arevalo-MartinA, et al.Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci. 2002; 22:9742–9753.
23.
HowlettAC. The cannabinoid receptors. Prostaglandins Other Lipid Mediat. 2002; 68–69:619–631.
24.
PertweeRG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther. 1997; 74:129–180.
25.
CrociT, ManaraL, AureggiG, et al.In vitro functional evidence of neuronal cannabinoid CB1 receptors in human ileum. Br J Pharmacol. 1998; 125:1393–1395.
26.
WagnerJA, JaraiZ, BatkaiS, et al.Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol. 2001; 423:203–210.
27.
MunroS, ThomasKL, Abu-ShaarM. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993; 365:61–65.
28.
PertweeRG. Cannabinoid receptors and pain. Prog Neurobiol. 2001; 63:569–611.
29.
GongJP, OnaiviES, IshiguroH, et al.Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006; 1071:10–23.
30.
ChenDJ, GaoM, GaoFF, et al.Brain cannabinoid receptor 2: expression, function and modulation. Acta Pharmacol Sin. 2017; 38:312–316.
31.
MareszK, CarrierEJ, PonomarevED, et al.Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem. 2005; 95:437–445.
32.
KleinTW, CabralGA. Cannabinoid-induced immune suppression and modulation of antigen-presenting cells. J Neuroimmune Pharmacol. 2006; 1:50–64.
33.
RomS, PersidskyY. Cannabinoid receptor 2: potential role in immunomodulation and neuroinflammation. J Neuroimmune Pharmacol. 2013; 8:608–620.
34.
DevaneWA, HanusL, BreuerA, et al.Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992; 258:1946–1949.
35.
MechoulamR, Ben-ShabatS, HanusL, et al.Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995; 50:83–90.
36.
SugiuraT, KondoS, SukagawaA, et al.2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995; 215:89–97.
37.
BisognoT, MelckD, BobrovM, et al.N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J. 2000; 351 Pt 3:817–824.
38.
PorterAC, SauerJM, KniermanMD, et al.Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther. 2002; 301:1020–1024.
39.
ZouS, KumarU. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018; 19:833.
40.
CristinoL, BisognoT, Di MarzoV. Cannabinoids and the expanded endocannabinoid system in neurological disorders. Nat Rev Neurol. 2020; 16:9–29.
41.
KanoM, Ohno-ShosakuT, HashimotodaniY, et al.Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009; 89:309–380.
42.
KatonaI, FreundTF. Multiple functions of endocannabinoid signaling in the brain. Annu Rev Neurosci. 2012; 35:529–558.
43.
LuHC, MackieK. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016; 79:516–525.
44.
Di MarzoV. Endocannabinoids: synthesis and degradation. Rev Physiol Biochem Pharmacol. 2008; 160:1–24.
45.
CastilloPE, YountsTJ, ChavezAE, et al.Endocannabinoid signaling and synaptic function. Neuron. 2012; 76:70–81.
46.
KatonaI, FreundTF. Endocannabinoid signaling as a synaptic circuit breaker in neurological disease. Nat Med. 2008; 14:923–930.
47.
AlgerBE, KimJ. Supply and demand for endocannabinoids. Trends Neurosci. 2011; 34:304–315.
48.
van der SteltM, Di MarzoV. Anandamide as an intracellular messenger regulating ion channel activity. Prostaglandins Other Lipid Mediat. 2005; 77:111–122.
49.
CravattBF, DemarestK, PatricelliMP, et al.Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci U S A. 2001; 98:9371–9376.
50.
BergerA, CrozierG, BisognoT, et al.Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proc Natl Acad Sci U S A. 2001; 98:6402–6406.
51.
Di MarzoV, FontanaA, CadasH, et al.Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994; 372:686–691.
52.
BeltramoM, PiomelliD. Carrier-mediated transport and enzymatic hydrolysis of the endogenous cannabinoid 2-arachidonylglycerol. Neuroreport. 2000; 11:1231–1235.
53.
MurataevaN, StraikerA, MackieK. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br J Pharmacol. 2014; 171:1379–1391.
54.
GulyasAI, CravattBF, BraceyMH, et al.Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci. 2004; 20:441–458.
55.
WestlakeTM, HowlettAC, BonnerTI, et al.Cannabinoid receptor binding and messenger RNA expression in human brain: an in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and Alzheimer's brains. Neuroscience. 1994; 63:637–652.
56.
FarkasS, NagyK, PalkovitsM, et al.[125I]SD-7015 reveals fine modalities of CB1 cannabinoid receptor density in the prefrontal cortex during progression of Alzheimer's disease. Neurochem Int. 2012; 60:286–291.
57.
KalifaS, PolstonEK, AllardJS, et al.Distribution patterns of cannabinoid CB1 receptors in the hippocampus of APPswe/PS1DeltaE9 double transgenic mice. Brain Res. 2011; 1376:94–100.
58.
BedseG, RomanoA, CianciS, et al.Altered expression of the CB1 cannabinoid receptor in the triple transgenic mouse model of Alzheimer's disease. J Alzheimers Dis. 2014; 40:701–712.
59.
VázquezC, TolónRM, GrandeMT, et al.Endocannabinoid regulation of amyloid-induced neuroinflammation. Neurobiol Aging. 2015; 36:3008–3019.
60.
StellaN. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010; 58:1017–1030.
61.
SolasM, FrancisPT, FrancoR, et al.CB2 receptor and amyloid pathology in frontal cortex of Alzheimer's disease patients. Neurobiol Aging. 2013; 34:805–808.
62.
SchmoleAC, LundtR, TernesS, et al.Cannabinoid receptor 2 deficiency results in reduced neuroinflammation in an Alzheimer's disease mouse model. Neurobiol Aging. 2015; 36:710–719.
63.
SchmöleA-C, LundtR, ToporowskiG, et al.Cannabinoid receptor 2-deficiency ameliorates disease symptoms in a mouse model with Alzheimer's disease-like pathology. J Alzheimers Dis. 2018; 64:379–392.
64.
NoonanJ, TanveerR, KlompasA, et al.Endocannabinoids prevent beta-amyloid-mediated lysosomal destabilization in cultured neurons. J Biol Chem. 2010; 285:38543–38554.
65.
MulderJ, ZilberterM, PasquaréSJ, et al.Molecular reorganization of endocannabinoid signalling in Alzheimer's disease. Brain. 2011; 134:1041–1060.
66.
KofalviA, LemosC, Martin-MorenoAM, et al.Stimulation of brain glucose uptake by cannabinoid CB2 receptors and its therapeutic potential in Alzheimer's disease. Neuropharmacology. 2016; 110:519–529.
67.
ChenR, ZhangJ, WuY, et al.Monoacylglycerol lipase is a therapeutic target for Alzheimer's disease. Cell Rep. 2012; 2:1329–1339.
68.
ManuelI, Gonzalez de San RomanE, GiraltMT, et al.Type-1 cannabinoid receptor activity during Alzheimer's disease progression. J Alzheimers Dis. 2014; 42:761–766.
69.
ZimmerER, ParentMJ, CuelloAC, et al.MicroPET imaging and transgenic models: a blueprint for Alzheimer's disease clinical research. Trends Neurosci. 2014; 37:629–641.
70.
AhmadR, GoffinK, Van den StockJ, et al.In vivo type 1 cannabinoid receptor availability in Alzheimer's disease. Eur Neuropsychopharmacol. 2014; 24:242–250.
71.
TakkinenJS, López-PicónFR, KirjavainenAK, et al.[(18)F]FMPEP-d(2) PET imaging shows age- and genotype-dependent impairments in the availability of cannabinoid receptor 1 in a mouse model of Alzheimer's disease. Neurobiol Aging. 2018; 69:199–208.
72.
HortiAG, GaoY, RavertHT, et al.Synthesis and biodistribution of [11C]A-836339, a new potential radioligand for PET imaging of cannabinoid type 2 receptors (CB2). Bioorg Med Chem. 2010; 18:5202–5207.
73.
AhmadR, PostnovA, BormansG, et al.Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2016; 43:2219–2227.
74.
VogelJW, YoungAL, OxtobyNP, et al.Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021; 27:871–881.
75.
MancusoR, Van Den DaeleJ, FattorelliN, et al.Stem-cell-derived human microglia transplanted in mouse brain to study human disease. Nat Neurosci. 2019; 22:2111–2116.
76.
FanZ, BrooksDJ, OkelloA, et al.An early and late peak in microglial activation in Alzheimer's disease trajectory. Brain. 2017; 140:792–803.
77.
HamillTG, LinLS, HagmannW, et al.PET imaging studies in rhesus monkey with the cannabinoid-1 (CB1) receptor ligand [11C]CB-119. Mol Imaging Biol. 2009; 11:246–252.
78.
WongDF, KuwabaraH, HortiAG, et al.Quantification of cerebral cannabinoid receptors subtype 1 (CB1) in healthy subjects and schizophrenia by the novel PET radioligand [11C]OMAR. Neuroimage. 2010; 52:1505–1513.
79.
SuterTM, ChesterfieldAK, BaoC, et al.Pharmacological characterization of the cannabinoid CB1 receptor PET ligand ortholog, [3H]MePPEP. Eur J Pharmacol. 2010; 649:44–50.
80.
NeumeisterA, NormandinMD, PietrzakRH, et al.Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: a positron emission tomography study. Mol Psychiatry. 2013; 18:1034–1040.
81.
LaurikainenH, TuominenL, TikkaM, et al.Sex difference in brain CB1 receptor availability in man. Neuroimage. 2019; 184:834–842.
82.
NormandinMD, ZhengMQ, LinKS, et al.Imaging the cannabinoid CB1 receptor in humans with [11C]OMAR: assessment of kinetic analysis methods, test-retest reproducibility, and gender differences. J Cereb Blood Flow Metab. 2015; 35:1313–1322.
83.
YamagishiS, IgaY, NakamuraM, et al.Upregulation of cannabinoid receptor type 2, but not TSPO, in senescence-accelerated neuroinflammation in mice: a positron emission tomography study. J Neuroinflammation. 2019; 16:208.
84.
WilsonAA, GarciaA, ParkesJ, et al.[11C]CURB: evaluation of a novel radiotracer for imaging fatty acid amide hydrolase by positron emission tomography. Nucl Med Biol. 2011; 38:247–253.
85.
SkaddanMB, ZhangL, JohnsonDS, et al.The synthesis and in vivo evaluation of [18F]PF-9811: a novel PET ligand for imaging brain fatty acid amide hydrolase (FAAH). Nucl Med Biol. 2012; 39:1058–1067.
86.
WangL, MoriW, ChengR, et al.Synthesis and preclinical evaluation of sulfonamido-based [(11)C-carbonyl]-carbamates and ureas for imaging monoacylglycerol lipase. Theranostics. 2016; 6:1145–1159.
87.
HortiAG, FanH, KuwabaraH, et al.11C-JHU75528: a radiotracer for PET imaging of CB1 cannabinoid receptors. J Nucl Med. 2006; 47:1689–1696.
88.
HeranceR, RojasS, AbadS, et al.Positron emission tomographic imaging of the cannabinoid type 1 receptor system with [11C]OMAR ([11C]JHU75528): improvements in image quantification using wild-type and knockout mice. Mol Imaging. 2011; 10:481–487.
89.
RanganathanM, Cortes-BrionesJ, RadhakrishnanR, et al.Reduced brain cannabinoid receptor availability in schizophrenia. Biol Psychiatry. 2016; 79:997–1005.
90.
BoileauI, RusjanPM, WilliamsB, et al.Blocking of fatty acid amide hydrolase activity with PF-04457845 in human brain: a positron emission tomography study with the novel radioligand [(11)C]CURB. J Cereb Blood Flow Metab. 2015; 35:1827–1835.
91.
RusjanPM, WilsonAA, MizrahiR, et al.Mapping human brain fatty acid amide hydrolase activity with PET. J Cereb Blood Flow Metab. 2013; 33:407–414.
92.
BoileauI, TyndaleRF, WilliamsB, et al.The fatty acid amide hydrolase C385A variant affects brain binding of the positron emission tomography tracer [11C]CURB. J Cereb Blood Flow Metab. 2015; 35:1237–1240.
93.
KoppelJ, BradshawH, GoldbergTE, et al.Endocannabinoids in Alzheimer's disease and their impact on normative cognitive performance: a case-control and cohort study. Lipids Health Dis. 2009; 8:2.
94.
AltamuraC, VentrigliaM, MartiniMG, et al.Elevation of plasma 2-arachidonoylglycerol levels in Alzheimer's disease patients as a potential protective mechanism against neurodegenerative decline. J Alzheimers Dis. 2015; 46:497–506.
95.
HillardCJ. Circulating endocannabinoids: from whence do they come and where are they going?. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology. 2018; 43:155–172.
96.
PascoalTA, BenedetAL, AshtonNJ, et al.Microglial activation and tau propagate jointly across Braak stages. Nat Med. 2021; 27:1592–1599.
97.
CakirM, TekinS, DoganyigitZ, et al.Cannabinoid type 2 receptor agonist JWH-133, attenuates Okadaic acid induced spatial memory impairment and neurodegeneration in rats. Life Sci. 2019; 217:25–33.
98.
WuJ, HocevarM, FossJF, et al.Activation of CB(2) receptor system restores cognitive capacity and hippocampal Sox2 expression in a transgenic mouse model of Alzheimer's disease. Eur J Pharmacol. 2017; 811:12–20.
99.
JayantS, SharmaBM, BansalR, et al.Pharmacological benefits of selective modulation of cannabinoid receptor type 2 (CB2) in experimental Alzheimer's disease. Pharmacol Biochem Behav. 2016; 140:39–50.
100.
Martin-MorenoAM, ReigadaD, RamirezBG, et al.Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease. Mol Pharmacol. 2011; 79:964–973.
101.
AsoE, Sanchez-PlaA, Vegas-LozanoE, et al.Cannabis-based medicine reduces multiple pathological processes in AbetaPP/PS1 mice. J Alzheimers Dis. 2015; 43:977–991.
102.
HillenJB, SoulsbyN, AldermanC, et al.Safety and effectiveness of cannabinoids for the treatment of neuropsychiatric symptoms in dementia: a systematic review. Ther Adv Drug Saf. 2019; 10:2042098619846993.
103.
MathewsWB, ScheffelU, FinleyP, et al.Biodistribution of [18F] SR144385 and [18F] SR147963: selective radioligands for positron emission tomographic studies of brain cannabinoid receptors. Nucl Med Biol. 2000; 27:757–762.
104.
MathewsWB, ScheffelU, RauseoPA, et al.Carbon-11 labeled radioligands for imaging brain cannabinoid receptors. Nucl Med Biol. 2002; 29:671–677.
105.
HortiAG, Van LaereK. Development of radioligands for in vivo imaging of type 1 cannabinoid receptors (CB1) in human brain. Curr Pharm Des. 2008; 14:3363–3383.
106.
VolkDW, EgganSM, HortiAG, et al.Reciprocal alterations in cortical cannabinoid receptor 1 binding relative to protein immunoreactivity and transcript levels in schizophrenia. Schizophr Res. 2014; 159:124–129.
107.
LeeJH, AgacinskiG, WilliamsJH, et al.Intact cannabinoid CB1 receptors in the Alzheimer's disease cortex. Neurochem Int. 2010; 57:985–989.
108.
EvensN, VandeputteC, MuccioliGG, et al.Synthesis, in vitro and in vivo evaluation of fluorine-18 labelled FE-GW405833 as a PET tracer for type 2 cannabinoid receptor imaging. Bioorg Med Chem. 2011; 19:4499–4505.
109.
SavonenkoAV, MelnikovaT, WangY, et al.Cannabinoid CB2 receptors in a mouse model of Aβ amyloidosis: immunohistochemical analysis and suitability as a PET biomarker of neuroinflammation. PLoS One. 2015; 10:e0129618.
110.
Van LaereK, GoffinK, CasteelsC, et al.Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [(18)F]MK-9470 PET. Neuroimage. 2008; 39:1533–1541.
111.
BurnsHD, Van LaereK, Sanabria-BohórquezS, et al.[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor. Proc Natl Acad Sci U S A. 2007; 104:9800–9805.
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