Alzheimer’s disease (AD), which is characterized by progressive brain dysfunction and memory loss, is one of the most significant global health concerns for older adults. Neuroinflammation and increased oxidative stress contribute to the pathophysiology of AD, thereby presumably inducing tryptophan (TRP) degradation through the TRP catabolite (TRYCAT) pathway.
Objective:
To delineate the activity of the TRYCAT pathway along with levels of TRP and tryptophan catabolites (TRYCATs) in AD patients.
Methods:
We used PubMed, Google Scholar, Web of Science, and SciFinder during the month of January 2022 to gather the pertinent publications. We found 19 eligible articles which involved 738 patients and 665 healthy controls.
Results:
Our results revealed a significant difference (p = 0.008) in the kynurenine (KYN)/TRP ratio (standardized mean difference, SMD = 0.216, 95% confidence interval, CI: 0.057; 0.376), and a significant decrease in TRP in AD patients (SMD = –0.520, 95% CI: –0.738; –0.302, p < 0.0001). Moreover, we also found a significant increase in the central nervous system (CNS), brain, and cerebrospinal fluid kynurenic acid (KA)/KYN ratio but not in peripheral blood, as well as a significant decrease in plasma KA and xanthurenic acid in the CNS and blood.
Conclusion:
AD is characterized by TRP depletion but not by an overactivity of the TRYCAT pathway. IDO-induced production of neurotoxic TRYCATs is not a key factor in the pathophysiology of AD.
O’BrienRJ, WongPC (2011) Amyloid precursor protein processing and Alzheimer’s disease. Annu Rev Neurosci34, 185–204.
6.
MattsonMP (2004) Pathways towards and away from Alzheimer’s disease. Nature430, 631–639.
7.
ChételatG, La JoieR, VillainN, PerrotinA, de La SayetteV, EustacheF, VandenbergheR (2013) Amyloid imaging in cognitively normal individuals, at-risk populations and preclinical Alzheimer’s disease. Neuroimage Clin2, 356–365.
8.
MorrisGP, ClarkIA, VisselB (2014) Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer’s disease. Acta Neuropathol Commun2, 135.
9.
GriffinWS, StanleyLC, LingC, WhiteL, MacLeodV, PerrotLJ, WhiteCL3rd, AraozC (1989) Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci U S A86, 7611–7615.
10.
HüllM, BergerM, VolkB, BauerJ (1996) Occurrence of interleukin-6 in cortical plaques of Alzheimer’s disease patients may precede transformation of diffuse into neuritic plaques. Ann N Y Acad Sci777, 205–212.
11.
BonaccorsoS, LinA, SongC, VerkerkR, KenisG, BosmansE, ScharpeS, VandewoudeM, DosscheA, MaesM (1998) Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer’s disease (DAT): Lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT. Aging (Milano)10, 316–323.
12.
van der WalEA, Gómez-PinillaF, CotmanCW (1993) Transforming growth factor-beta 1 is in plaques in Alzheimer and Down pathologies. Neuroreport4, 69–72.
BrosseronF, KrauthausenM, KummerM, HenekaMT (2014) Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: A comparative overview. Mol Neurobiol50, 534–544.
15.
MaesM, DeVosN, WautersA, DemedtsP, MauritsV, NeelsH, BosmansE, AltamuraC, LinA, SongC, VandenbrouckeM, ScharpeS (1999) Inflammatory markers in younger vs elderly normal volunteers and in patients with Alzheimer’s disease. J Psychiatr Res33, 397–405.
16.
ZvěřováM, FišarZ, JirákR, KitzlerováE, HroudováJ, RabochJ (2013) Plasma cortisol in Alzheimer’s disease with or without depressive symptoms. Med Sci Monit19, 681–689.
17.
BelkhelfaM, RafaH, MedjeberO, Arroul-LammaliA, BehairiN, Abada-BendibM, MakreloufM, BelarbiS, MasmoudiAN, TazirM, Touil-BoukoffaC (2014) IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: A study in Algerian patients. J Interferon Cytokine Res34, 839–847.
18.
MaesM, GaleckiP, ChangYS, BerkM (2011) A review on the oxidative and nitrosative stress (O&NS) pathways in major depression and their possible contribution to the (neuro)degenerative processes in that illness. Prog Neuropsychopharmacol Biol Psychiatry35, 676–692.
19.
MoneimAE (2015) Oxidant/Antioxidant imbalance and the risk of Alzheimer’s disease. Curr Alzheimer Res12, 335–349.
20.
KimHS, KimS, ShinSJ, ParkYH, NamY, KimCW, LeeKW, KimSM, JungID, YangHD, ParkYM, MoonM (2021) Gram-negative bacteria and their lipopolysaccharides in Alzheimer’s disease: Pathologic roles and therapeutic implications. Transl Neurodegener10, 49.
ZhaoY, JaberV, LukiwWJ (2017) Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): Detection of Lipopolysaccharide (LPS) in AD hippocampus. Front Cell Infect Microbiol7, 318.
HalawaAA, A El-AdlM, HamedMF, BalboulaAZ, ElmetwallyMA, DiKB (2018) Lipopolysaccharide prompts oxidative stress and apoptosis in rats’ testicular tissue. J Vet Healthc1, 20–31.
25.
MaesM, LeonardBE, MyintAM, KuberaM, VerkerkR (2011) The new ’5-HT’ hypothesis of depression: Cell-mediated immune activation induces indoleamine 2,3-dioxygenase, which leads to lower plasma tryptophan and an increased synthesis of detrimental tryptophan catabolites (TRYCATs), both of which contribute to the onset of depression. Prog Neuropsychopharmacol Biol Psychiatry35, 702–721.
26.
SmithRS, MaesM (1995) The macrophage-T-lymphocyte theory of schizophrenia: Additional evidence. Med Hypotheses45, 135–141.
27.
KanchanatawanB, SirivichayakulS, RuxrungthamK, CarvalhoAF, GeffardM, AndersonG, MaesM (2018) Deficit schizophrenia is characterized by defects in IgM-mediated responses to Tryptophan Catabolites (TRYCATs): A paradigm shift towards defects in natural self-regulatory immune responses coupled with mucosa-derived TRYCAT pathway activation. Mol Neurobiol55, 2214–2226.
28.
MaesM, MeltzerHY, ScharpéS, BosmansE, SuyE, De MeesterI, CalabreseJ, CosynsP (1993) Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Res49, 151–165.
29.
WidnerB, LeblhuberF, WalliJ, TilzGP, DemelU, FuchsD (2000) Tryptophan degradation and immune activation in Alzheimer’s disease. J Neural Transm (Vienna)107, 343–353.
30.
GreilbergerJ, FuchsD, LeblhuberF, GreilbergerM, WintersteigerR, TafeitE (2010) Carbonyl proteins as a clinical marker in Alzheimer’s disease and its relation to tryptophan degradation and immune activation. Clin Lab56, 441–448.
31.
RadulescuI, DragoiAM, TrifuSC, CristeaMB (2021) Neuroplasticity and depression: Rewiring the brain’s networks through pharmacological therapy (Review). Exp Ther Med22, 1131.
32.
CroonenberghsJ, VerkerkR, ScharpeS, DeboutteD, MaesM (2005) Serotonergic disturbances in autistic disorder: L-5-hydroxytryptophan administration to autistic youngsters increases the blood concentrations of serotonin in patients but not in controls. Life Sci76, 2171–2183.
33.
GoldsteinLE, LeopoldMC, HuangX, AtwoodCS, SaundersAJ, HartshornM, LimJT, FagetKY, MuffatJA, ScarpaRC, ChylackLTJr, BowdenEF, TanziRE, BushAI (2000) 3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction. Biochemistry39, 7266–7275.
34.
SmithAJ, SmithRA, StoneTW (2009) 5-Hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones. Neurotox Res15, 303–310.
35.
ZadoriD, VeresG, SzalardyL, KlivenyiP, VecseiL (2018) Alzheimer’s disease: Recent concepts on the relation of mitochondrial disturbances, excitotoxicity, neuroinflammation, and kynurenines. J Alzheimers Dis62, 523–547.
36.
OkudaS, NishiyamaN, SaitoH, KatsukiH (1998) 3-Hydroxykynurenine, an endogenous oxidative stress generator, causes neuronal cell death with apoptotic features and region selectivity. J Neurochem70, 299–307.
37.
DykensJA, SullivanSG, SternA (1987) Oxidative reactivity of the tryptophan metabolites 3-hydroxyanthranilate, cinnabarinate, quinolinate and picolinate. Biochem Pharmacol36, 211–217.
38.
SantamaríaA, Galván-ArzateS, LisýV, AliSF, DuhartHM, Osorio-RicoL, RíosC, St’astnýF (2001) Quinolinic acid induces oxidative stress in rat brain synaptosomes. Neuroreport12, 871–874.
39.
RiosC, SantamariaA (1991) Quinolinic acid is a potent lipid peroxidant in rat brain homogenates. Neurochem Res16, 1139–1143.
40.
KanchanatawanB, SirivichayakulS, RuxrungthamK, CarvalhoAF, GeffardM, OrmstadH, AndersonG, MaesM (2018) Deficit, but not nondeficit, schizophrenia is characterized by mucosa-associated activation of the Tryptophan Catabolite (TRYCAT) pathway with highly specific increases in IgA responses directed to picolinic, xanthurenic, and quinolinic acid. Mol Neurobiol55, 1524–1536.
41.
MorrisG, CarvalhoAF, AndersonG, GaleckiP, MaesM (2016) The many neuroprogressive actions of Tryptophan Catabolites (TRYCATs) that may be associated with the pathophysiology of neuro-immune disorders. Curr Pharm Des22, 963–977.
42.
AlmullaAF, MaesM (2022) The tryptophan catabolite or kynurenine pathway’s role in major depression. Curr Top Med Chem22, 10.2174/1568026622666220428095250.
43.
GuilleminGJ, CullenKM, LimCK, SmytheGA, GarnerB, KapoorV, TakikawaO, BrewBJ (2007) Characterization of the kynurenine pathway in human neurons. J Neurosci27, 12884–12892.
44.
AlmullaAF, VasupanrajitA, TunvirachaisakulC, Al-HakeimHK, SolmiM, VerkerkR, MaesM (2022) The tryptophan catabolite or kynurenine pathway in schizophrenia: Meta-analysis reveals dissociations between central, serum, and plasma compartments. Mol Psychiatry. doi: 10.1038/s41380-022-01552-4.
45.
WanX, WangW, LiuJ, TongT (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol14, 135.
46.
CohenJ (2013), Statistical power analysis for the behavioral sciences, Academic Press.
47.
VasupanrajitA, JirakranK, TunvirachaisakulC, SolmiM, MaesM (2022) Inflammation and nitro-oxidative stress in current suicidal attempts and current suicidal ideation: A systematic review and meta-analysis. Mol Psychiatry27, 1350–1361.
48.
VasupanrajitA, JirakranK, TunvirachaisakulC, MaesM (2021) Suicide attempts are associated with activated immune-inflammatory, nitro-oxidative, and neurotoxic pathways: A systematic review and meta-analysis. J Affect Disord295, 80–92.
Gonzalez-SanchezM, JimenezJ, NarvaezA, AntequeraD, Llamas-VelascoS, MartinAH, ArjonaJAM, MunainAL, BisaAL, MarcoMP, Rodriguez-NunezM, Perez-MartinezDA, Villarejo-GalendeA, BartolomeF, DominguezE, CarroE (2020) Kynurenic acid levels are increased in the CSF of Alzheimer’s disease patients. Biomolecules10, 571.
52.
GulajE, PawlakK, BienB, PawlakD (2010) Kynurenine and its metabolites in Alzheimer’s disease patients. Adv Med Sci55, 204–211.
53.
HartaiZ, JuhaszA, RimanoczyA, JanakyT, DonkoT, DuxL, PenkeB, TothGK, JankaZ, KalmanJ (2007) Decreased serum and red blood cell kynurenic acid levels in Alzheimer’s disease. Neurochem Int50, 308–313.
54.
JacobsKR, LimCK, BlennowK, ZetterbergH, ChatterjeeP, MartinsRN, BrewBJ, GuilleminGJ, LovejoyDB (2019) Correlation between plasma and CSF concentrations of kynurenine pathway metabolites in Alzheimer’s disease and relationship to amyloid-beta and tau. Neurobiol Aging80, 11–20.
55.
RommerPS, FuchsD, LeblhuberF, SchrothR, GreilbergerM, TafeitE, GreilbergerJ (2016) Lowered levels of carbonyl proteins after vitamin B supplementation in patients with mild cognitive impairment and Alzheimer’s disease. Neurodegener Dis16, 284–289.
SorgdragerFJH, VermeirenY, Van FaassenM, van der LeyC, NollenEAA, KemaIP, De DeynPP (2019) Age- and disease-specific changes of the kynurenine pathway in Parkinson’s and Alzheimer’s disease. J Neurochem151, 656–668.
58.
TohgiH, AbeT, TakahashiS, KimuraM, TakahashiJ, KikuchiT (1992) Concentrations of serotonin and its related substances in the cerebrospinal fluid in patients with Alzheimer type dementia. Neurosci Lett141, 9–12.
59.
TohgiH, AbeT, TakahashiS, SahekiM, KimuraM (1995) Indoleamine concentrations in cerebrospinal fluid from patients with Alzheimer type and Binswanger type dementias before and after administration of citalopram, a synthetic serotonin uptake inhibitor. J Neural Transm Park Dis Dement Sect9, 121–131.
60.
van der VelpenV, TeavT, Gallart-AyalaH, MehlF, KonzI, ClarkC, OikonomidiA, PeyratoutG, HenryH, DelorenziM, IvanisevicJ, PoppJ (2019) Systemic and central nervous system metabolic alterations in Alzheimer’s disease. Alzheimers Res Ther11, 93.
61.
WennstromM, NielsenHM, OrhanF, LondosE, MinthonL, ErhardtS (2014) Kynurenic Acid levels in cerebrospinal fluid from patients with Alzheimer’s disease or dementia with lewy bodies. Int J Tryptophan Res7, 1–7.
62.
WhileyL, ChappellKE, D’HondtE, LewisMR, JimenezB, SnowdenSG, SoininenH, KloszewskaI, MecocciP, TsolakiM, VellasB, SwannJR, HyeA, LovestoneS, Legido-QuigleyC, HolmesE; AddNeuroMed consortium (2021) Metabolic phenotyping reveals a reduction in the bioavailability of serotonin and kynurenine pathway metabolites in both the urine and serum of individuals living with Alzheimer’s disease. Alzheimers Res Ther13, 20.
63.
WilletteAA, PappasC, HothN, WangQ, KlinedinstB, WilletteSA, LarsenB, PollpeterA, LiT, LeS, Collazo-MartinezAD, MochelJP, AllenspachK, DantzerR; Alzheimer’s Disease Neuroimaging Initiative (2021) Inflammation, negative affect, and amyloid burden in Alzheimer’s disease: Insights from the kynurenine pathway. Brain Behav Immun95, 216–225.
KimJW, ByunMS, LeeJH, YiD, JeonSY, SohnBK, LeeJY, ShinSA, KimYK, KangKM, SohnCH, LeeDY; KBASE Research Group (2020) Serum albumin and beta-amyloid deposition in the human brain. Neurology95, e815–e826.
66.
MaesM, WautersA, VerkerkR, DemedtsP, NeelsH, Van GastelA, CosynsP, ScharpéS, DesnyderR (1996) Lower serum L-tryptophan availability in depression as a marker of a more generalized disorder in protein metabolism. Neuropsychopharmacology15, 243–251.
67.
RuhéHG, MasonNS, ScheneAH (2007) Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: A meta-analysis of monoamine depletion studies. Mol Psychiatry12, 331–359.
68.
HoodSD, BellCJ, NuttDJ (2005) Acute tryptophan depletion. Part I: Rationale and methodology. Aust N Z J Psychiatry39, 558–564.
69.
Del Angel-MezaAR, Dávalos-MarínAJ, Ontiveros-MartinezLL, OrtizGG, Beas-ZarateC, Chaparro-HuertaV, Torres-MendozaBM, Bitzer-QuinteroOK (2011) Protective effects of tryptophan on neuro-inflammation in rats after administering lipopolysaccharide. Biomed Pharmacother65, 215–219.
70.
HodgkinsPS, SchwarczR (1998) Interference with cellular energy metabolism reduces kynurenic acid formation in rat brain slices: Reversal by lactate and pyruvate. Eur J Neurosci10, 1986–1994.
71.
HughesTD, GunerOF, IradukundaEC, PhillipsRS, BowenJP (2022) The kynurenine pathway and kynurenine 3-monooxygenase inhibitors. Molecules27, 273.
72.
Fragoso-MoralesLG, Correa-BasurtoJ, Rosales-HernandezMC (2021) Implication of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and its inhibitors in Alzheimer’s disease murine models. Antioxidants (Basel)10, 218.
73.
Lugo-HuitrónR, Ugalde MuñizP, PinedaB, Pedraza-ChaverríJ, RíosC, Pérez-de la CruzV (2013) Quinolinic acid: An endogenous neurotoxin with multiple targets. Oxid Med Cell Longev2013, 104024.
74.
RahmanA, TingK, CullenKM, BraidyN, BrewBJ, GuilleminGJ (2009) The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One4, e6344.
75.
MoroniF (1999) Tryptophan metabolism and brain function: Focus on kynurenine and other indole metabolites. Eur J Pharmacol375, 87–100.
76.
ChourakiV, PreisSR, YangQ, BeiserA, LiS, LarsonMG, WeinsteinG, WangTJ, GersztenRE, VasanRS, SeshadriS (2017) Association of amine biomarkers with incident dementia and Alzheimer’s disease in the Framingham Study. Alzheimers Dement13, 1327–1336.
77.
ChatterjeeP, GoozeeK, LimCK, JamesI, ShenK, JacobsKR, SohrabiHR, ShahT, AsihPR, DaveP, ManYanC, TaddeiK, LovejoyDB, ChungR, GuilleminGJ, MartinsRN (2018) Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-beta load: A pilot study. Sci Rep8, 8008.
78.
OxenkrugGF, GurevichD, SiegelB, DumlaoMS, GershonS (1989) Correlation between brain-adrenal axis activation and cognitive impairment in alzheimer’s disease: Is there a gender effect?Psychiatry Res29, 169–175.
79.
SongT, SongX, ZhuC, PatrickR, SkurlaM, SantangeloI, GreenM, HarperD, RenB, ForesterBP, ÖngürD, DuF (2021) Mitochondrial dysfunction, oxidative stress, neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies. Ageing Res Rev72, 101503.
80.
ShenXN, NiuLD, WangYJ, CaoXP, LiuQ, TanL, ZhangC, YuJT (2019) Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: A meta-analysis and systematic review of 170 studies. J Neurol Neurosurg Psychiatry90, 590–598.
81.
SchragM, MuellerC, ZabelM, CroftonA, KirschWM, GhribiO, SquittiR, PerryG (2013) Oxidative stress in blood in Alzheimer’s disease and mild cognitive impairment: A meta-analysis. Neurobiol Dis59, 100–110.
82.
StojanovD (2006) On the molecular correlations in the pathobiochemistry of Alzheimer disease. Biotechnol Biotechnol Equip20, 17–23.
