Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of ß-amyloid aggregation.

Autor:	Meek AR; Department of Chemistry, Dalhousie University, Halifax, NS, Canada., Simms GA, Weaver DF
Jazyk:	angličtina
Zdroj:	Journal of psychiatry & neuroscience : JPN [J Psychiatry Neurosci] 2013 Jul; Vol. 38 (4), pp. 269-75.
DOI:	10.1503/jpn.120166
Abstrakt:	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 ß-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 histidine(13)-histidine-glutamine-lysine(16) (HHQK) region of ß-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 ß-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 ß-amyloid that leads to protein misfolding and neurotoxicity. Both L-PS and 3-HAA were able to inhibit ß-amyloid aggregation in varying concentrations; levels of these compounds in the brain may impact their effectiveness in slowing/preventing ß-amyloid aggregation.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu