@article {Meek269, author = {Autumn R. Meek and Gordon A. Simms and Donald F. Weaver}, title = {2011 CCNP Heinz Lehman Award paper: Searching for an endogenous anti-Alzheimer molecule: identifying small molecules in the brain that slow Alzheimer disease progression by inhibition of β-amyloid aggregation}, volume = {38}, number = {4}, pages = {269--275}, year = {2013}, doi = {10.1503/jpn.120166}, publisher = {Journal of Psychiatry and Neuroscience}, 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{\textendash}histidine{\textendash}glutamine{\textendash}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.}, issn = {1180-4882}, URL = {https://www.jpn.ca/content/38/4/269}, eprint = {https://www.jpn.ca/content/38/4/269.full.pdf}, journal = {Journal of Psychiatry and Neuroscience} }