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

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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J Psychiatry Neurosci 2013; 38(4): 269-275

Autumn R. Meek, PhD; Gordon A. Simms, BSc; Donald F. Weaver, MD, PhD

Meek, Simms, Weaver — Department of Chemistry, Dalhousie University; Weaver — Division of Neurology, Department of Medicine and Department of Biomedical Engineering, Dalhousie University, Halifax, NS, Canada

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.


Submitted Aug. 22, 2012; Revised Oct. 19, 24, 2012; Accepted Oct. 29, 2012.

Acknowledgements: This research was funded by the Nova Scotia Health Research Foundation (A.R. Meek), the Gunn Family Studentship in Alzheimer’s Research (A.R. Meek), the Alzheimer’s Society of Canada (G.A. Simms) and Canadian Institutes for Health Research (operating grant to D.F. Weaver and studentship to G.A. Simms). The in vitro assays were performed by Todd Galloway and Rose Chen.

Competing interests: As above. D.F. Weaver also declares holding stock in Trevent is Corporation.

Contributors: A. Meek and D.F. Weaver designed the study. A.Meek and G.A. Simms acquired the data, which all authors analyzed. All authors wrote and reviewed the article and approved the final version for publication.

DOI: 10.1503/jpn.120166

Correspondence to: D.F. Weaver, Department of Chemistry, Dalhousie University, 6274 Coburg Rd, PO Box 15000, Halifax NS B3H 4R2; donald.weaver@dal.ca