Searching for an endogenous anti-alzheimer molecule: Identifying small molecules in the brain that slow alzheimer disease progression by inhibition of β-amyloid aggregation

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Abstract

Background: Alzheimer disease is a neurodegenerative disorder that progresses with marked interindividual clinical variability. We postulate the existence of endogenous molecules within the human brain exerting an antiaggregant activity that will prevent/slow Alzheimer disease progression. Methods: We performed in silico studies to determine if the small endogenous molecules L-phosphoserine (L-PS) and 3-hydroxyanthranilic acid (3-HAA) could bind to the target region of β-amyloid responsible for protein misfolding. In vitro assays measured the antiaggregation effect of these molecules at varying concentrations. Results: In silico studies demonstrated that L-PS and 3-HAA, both endogenous brain molecules, were capable of binding to the histidine13-histidine-glutamine-lysine16(HHQK) region of β-amyloid involved in misfolding: these interactions were energetically favoured. The in vitro assays showed that both L-PS and 3-HAA were capable of inhibiting β-amyloid aggregation in a dose-dependent manner, with 3-HAA being more potent than L-PS. Limitations: Studies were performed in silico and in vitro but not in vivo. Conclusion: We successfully identified 2 endogenous brain molecules, L-PS and 3-HAA, that were capable of binding to the region of β-amyloid that leads to protein misfolding and neurotoxicity. Both L-PS and 3-HAA were able to inhibit β-amyloid aggregation in varying concentrations; levels of these compounds in the brain may impact their effectiveness in slowing/preventing β-amyloid aggregation.

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Meek, A. R., Simms, G. A., & Weaver, D. F. (2013). Searching for an endogenous anti-alzheimer molecule: Identifying small molecules in the brain that slow alzheimer disease progression by inhibition of β-amyloid aggregation. Journal of Psychiatry and Neuroscience, 38(4), 269–275. https://doi.org/10.1503/jpn.120166

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