Fig. 1.Tryptophan-melatonin pathway interactions. Shows the
tryptophan-melatonin pathway (green shade) and how it is intimately linked to key
systemic processes relevant to dementia pathoetiology, including: (1) Stress/HPA
axis activity drives GR activation and GR/TDO-kynurenine/AhR induction. Stress/GR
drives gut-derived LPS and other TLR2/4 activators that upregulate the
transcription factors, NF-kB and YY1, thereby inducing-BACE1-amyloid-
and hyperphosphorylated tau; (2) white adipocyte (WAT)-derived kynurenine
activates the AhR as well as inducing neurotoxic kynurenine pathway products; and
(3) gut microbiome-derived butyrate and circadian melatonin upregulates sirtuin-3
to disinhibit PDC, thereby optimizing mitochondrial function, whilst also
providing acetyl-CoA as a necessary cosubstrate for the conversion of serotonin
to NAS in the initiation of the melatonergic pathway. Tryptophan is mainly
diet-derived but is also produced by the shikimate pathway of the gut microbiome.
The large amino acid transporter (LAT)-1 takes circulating tryptophan into cells,
including astrocytes, with TPH1 and TPH2 needing to be stabilized by 14-3-3e to
allow tryptophan to be converted to 5-HTP. AADC then converts 5-HTP to 5-HT
(serotonin). 14-3-3z stabilized AANAT metabolizes 5-HT to N-acetylserotonin
(NAS), in the presence of acetyl-CoA as a necessary cosubstrate. NAS is converted
to melatonin by ASMT. Acetyl-CoA levels are highly dependent upon optimized
mitochondrial function arising from PDC disinhibition allowing the induction of
the mitochondrial melatonergic pathway to be intimately linked to mitochondrial
metabolic function. Pineal melatonin and the gut microbiome-derived short-chain
fatty acid, butyrate, induce sirtuin-3, which deacetylates and disinhibits PDC,
thereby enhancing the conversion of pyruvate to acetyl-CoA. Stress/CRH/GR
activation and pro-inflammatory cytokines suppress pineal melatonin and increase
gut permeability/dysbiosis, thereby lowering butyrate levels. The AhR, via CYP1A2
and CYP1B1, can O-demethylates melatonin to NAS, with AhR induced
CYP1B1/CYP1A2/CYP1A1 also able to hydroxylate melatonin to 6-hydroxymelatonin via
modifiable protein-protein interactions. The AhR can therefore suppress melatonin
by a couple of processes as well as raising the CYP1NAS/melatonin ratio. NAS and
melatonin have many common but important differential effects given that NAS
activates the BDNF receptor, TrkB, as well as inducing BDNF, being a couple of
means whereby NAS enhances TrkB activation. TrkB activation may be beneficial in
dementia, although this may be dependent upon the full-length (TrkB-FL) isoform
as the truncated isoform (TrkB-T1) can contribute to apoptosis. Notably, TrkB-FL
and TrkB-T1 effects will be dependent upon location on the mitochondrial and/or
plasma membranes. Melatonin affords powerful protection in dementia models,
partly mediated by its suppression of the gut-permeability associated LPS and GR
nuclear translocation, thereby preventing the GR from inducing TDO-kynurenine and
BACE1-amyloid-. Melatonin also suppresses hyperphosphorylated-tau both
directly and via decreased amyloid-. Melatonin also stimulates the
non-amyloidogenic -secretase activities of ADAM10 and ADAM17, whilst
inhibiting the expression of the amyloidogenic - and
-secretases. The melatonergic pathway is therefore in intimate
interactions with systemic processes linked to dementia, with the incapacity of
NF-kB and YY1 to induce melatonin from the melatonergic pathway (red shade X)
being crucial to dementia pathophysiology. Abbreviations: 5-HT, serotonin;
5-HTTP, 5-hydroxytryptophan; AADC, aromatic-L-amino acid decarboxylase;
acetyl-CoA, acetyl-coenzyme A; AANAT, aralkylamine N-acetyltransferase; AhR, aryl
hydrocarbon receptor; ASMT, N-acetylserotonin O-methyltransferase; BACE1,
-site amyloid precursor protein-cleaving enzyme 1; BDNF, brain-derived
neurotrophic factor; CRH, corticotrophin releasing hormone; CYP, cytochrome P450;
GR, glucocorticoid receptor; HPA, hypothalamus-pituitary-adrenal; LAT-1, large
amino acid transporter 1; LPS, lipopolysaccharide; NAS, N-acetylserotonin; NF-kB,
nuclear factor kappa-light-chain-enhancer of activated B cells; TLR, toll-like
receptor; TrkB-FL, tyrosine receptor kinase B-full length; TrkB-T1, tyrosine
receptor kinase B-truncated; TDO, tryptophan 2,3-dioxygenase; PDC, pyruvate
dehydrogenase complex; ADAM, A disintegrin and metalloproteinase domain-containing protein; YY, yin yang.