The Role of Tryptophan Metabolism in Alzheimer's Disease

The need to identify new potentially druggable biochemical mechanisms for Alzheimer's disease (AD) is an ongoing priority. The therapeutic limitations of amyloid-based approaches are further motivating this search. Amino acid metabolism, particularly tryptophan metabolism, has the potential to emerge as a leading candidate and an alternative exploitable biomolecular target. Multiple avenues support this contention. Tryptophan (trp) and its associated metabolites are able to inhibit various enzymes participating in the biosynthesis of beta-amyloid, and one metabolite, 3-hydroxyanthranilate, is able to directly inhibit neurotoxic beta-amyloid oligomerization; however, whilst certain trp metabolites are neuroprotectant, other metabolites, such as quinolinic acid, are directly toxic to neurons and may themselves contribute to AD progression. Trp metabolites also have the ability to influence microglia and associated cytokines in order to modulate the neuroinflammatory and neuroimmune factors which trigger pro-inflammatory cytotoxicity in AD. Finally, trp and various metabolites, including melatonin, are regulators of sleep, with disorders of sleep being an important risk factor for the development of AD. Thus, the involvement of trp biochemistry in AD is multifactorial and offers a plethora of druggable targets in the continuing quest for AD therapeutics.

Automated summary

The search for new biochemical mechanisms for treating Alzheimer's disease is essential due to the limitations of current amyloid-based approaches. Amino acid metabolism, specifically tryptophan metabolism, is a potential alternative biological target. Tryptophan and its metabolites can inhibit enzymes involved in beta-amyloid synthesis and directly inhibit neurotoxic beta-amyloid oligomerization. Additionally, tryptophan metabolites can affect microglia and associated cytokines, contributing to neuroinflammation in Alzheimer's disease. The involvement of tryptophan biochemistry in Alzheimer's disease offers multiple druggable targets in the quest for therapeutics.