A More Holistic Perspective of Alzheimer's Disease: Roles of Gut Microbiome, Adipocytes, HPA Axis, Melatonergic Pathway and Astrocyte Mitochondria in the Emergence of Autoimmunity

George Anderson^1,*

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¹ CRC Scotland & London, SW1V 1PG London, UK

^*Correspondence: anderson.george@rocketmail.com (George Anderson)

Front. Biosci. (Landmark Ed) 2023, 28(12), 355; https://doi.org/10.31083/j.fbl2812355

Submitted: 30 August 2023 | Revised: 14 October 2023 | Accepted: 27 October 2023 | Published: 28 December 2023

(This article belongs to the Special Issue Exploring Pathomechanisms, Novel Targets, and New Interventions for Neurological and Neuropsychiatric Disorders)

This is an open access article under the CC BY 4.0 license.

Abstract

Alzheimer’s disease is widely regarded as poorly treated due to poor conceptualization. For 40 years, Alzheimer’s disease pathophysiology has focused on two culprits, amyloid- $\beta{}$ induced plaques and hyperphosphorylated tau associated tangles, with no significant treatment advance. This is confounded by data showing amyloid- $\beta{}$ to be an endogenous antimicrobial that is increased in a wide array of diverse medical conditions associated with heightened inflammation. This article reviews the wider bodies of data pertaining to Alzheimer’s disease pathophysiology, highlighting the role of suppressed astrocyte mitochondrial function and mitochondrial melatonergic pathway as a core hub in driving neuronal loss in dementia. It is proposed that astrocyte function over aging becomes dysregulated, at least partly mediated by systemic processes involving the 10-fold decrease in pineal melatonin leading to the attenuated capacity of night-time melatonin to dampen residual daytime inflammation. Suppressed pineal melatonin also attenuates melatonin’s inhibition of glucocorticoid receptor nuclear translocation, thereby changing not only stress/hypothalamus-pituitary-adrenal (HPA) axis consequences but also the consequences of the cortisol awakening response, which ‘primes the body for the coming day’. Gut microbiome-derived butyrate also inhibits glucocorticoid receptor nuclear translocation, as well as inducing the mitochondrial melatonergic pathway. It is proposed that the loss of astrocyte melatonin prevents the autocrine and paracrine effects of melatonin in limiting amyloid- $\beta{}$ levels and effects. Suppressed astrocyte melatonin production also attenuates the melatonin induction of astrocyte lactate, thereby decreasing neuronal mitochondrial metabolism and the neuronal mitochondrial melatonergic pathway. The loss of astrocyte lactate and melatonin, coupled to the suppression of neuronal mitochondrial metabolism and melatonin production decreases mitophagy, leading to the induction of the major histocompatibility complex (MHC)-1. MHC-1 initiates the chemoattraction of CD8 ${}^{+}$ t cells, leading to neuronal destruction in Alzheimer’s disease being driven by ‘autoimmune’/‘immune-mediated’ processes. Alzheimer’s disease may therefore be conceptualized as being initiated by systemic processes that act on astrocytes as a core hub, with the suppression of the astrocyte melatonergic pathway leaving neurons deplete of appropriate metabolic substrates and co-ordinated antioxidants. This culminates in an ‘immune-mediated’ cell death. Future research and treatment/prevention implications are indicated.

Keywords

Alzheimer's disease

gut microbiome

melatonin

N-acetylserotonin

aryl hydrocarbon receptor

kynurenine

HPA axis

glucocorticoid receptor

adipocytes

treatment

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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- $\beta{}$ 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- $\beta{}$ . Melatonin also suppresses hyperphosphorylated-tau both directly and via decreased amyloid- $\beta{}$ . Melatonin also stimulates the non-amyloidogenic $\alpha{}$ -secretase activities of ADAM10 and ADAM17, whilst inhibiting the expression of the amyloidogenic $\beta{}$ - and $\gamma{}$ -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, $\beta{}$ -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.

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