3.1. Trp and Proteopathy in AD

While the causative contributions of the ‘amyloid hypothesis’ to AD have come into question in recent years, deposits of misfolded Aβ oligomers and higher-order aggregates (e.g., fibrils), the so-called amyloid plaques, are strongly correlated with the well-described neuropathology of AD [4]. β-Amyloid aggregates (particularly small oligomers) are generally considered to be neurotoxic and neuroinflammatory, and even if not the root cause of AD, have a pronounced cytotoxic effect and possibly contribute to disease progression [13].

The biosynthesis of Aβ has received considerable study. Amyloid precursor protein (APP) is cleaved by amyloid secretase, an enzyme with several variants that cleave APP at the designated α, β and γ sites [4]. Generally, APP may be cleaved either by α-secretase, or alternatively by β-secretase then γ-secretase [4], with this latter route being responsible for the production of sAPPβ and the Aβ monomer. APP cleaving is thought to be competitive, suggesting that Aβ deposition could be downregulated by increasing the production of the α-secretase, as the α cleavage site is within the Aβ domain, and hence, sAPPα cannot produce Aβ [14]. There has been interest in α-secretase as a therapeutic target as sAPPα has potent neuroprotective actions against glutamate neurotoxicity, Aβ peptide-induced oxidative injury, and glucose deprivation. The investigation of sAPPα as a therapeutic target has indicated that trp’s serotonergic signaling pathways in the CNS are involved in the upregulation of α-secretase production; moreover, 5-HT4 agonists stimulate increased α-secretase production, as well as reduced amyloid burden and decreased neuroinflammation, indicating that sAPPα inhibition may have some efficacy in mitigating the pathology of AD progression [15].

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In terms of other trp-influenced enzymes implicated in Aβ biochemistry, neprilysin (NEP) is a metalloproteinase regulating the brain clearance of Aβ peptides; a decrease in Aβ elimination may be a significant contributor to AD pathogenesis [16]. Two trp metabolites, 5-hydroxyindole-acetic acid (5-HIAA) and KYNA, stimulate NEP activity/expression to prevent Aβ peptide-induced neurotoxicity, possibly by interacting with the aryl hydrocarbon receptor. These data suggest promising perspectives for the design of a tryptophan metabolite-based enzyme targeting therapies against AD [17].

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In addition to trp metabolism’s influence on enzymes involved in the biosynthesis of Aβ, various trp metabolites have also demonstrated the ability to directly inhibit Aβ oligomerization and aggregation. The trp metabolite 3-hydroxyanthranilic acid, generated via the kynurenic pathway, has the capacity to function as an endogenous inhibitor of Aβ aggregation [18].

Therefore, trp and trp metabolites are able to modulate Aβ biochemistry in a potentially beneficial manner by interacting with various enzymes, including α-secretase and neprilysin, and by directly interacting with Aβ itself.

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