Understanding the inhibition of age-induced neurotoxic A β -oligomers

Age is a major risk factor for Alzheimer’s Disease (AD), which currently has no cure. Recent clinical trials have shown that suppressing soluble oligomers formed by an endogenous peptide called A β significantly slows AD progression. Targeting A β oligomers rely on antibodies that lead to severe side effects, including possibly fatal brain bleeding.
Aging significantly reduces the levels of Adenosine Triphosphate (ATP), which prevents A β self-association through a mechanism unknown because of the inherently transient nature of the A β oligomers. It is critical to find alternative approaches to safely decrease toxic A β oligomers built up during aging.
The goal of the proposed project is to dissect the mechanism of action of ATP and other nucleotides as A β oligomerization inhibitors by using spectroscopic methods recently developed by the research team, aiming to accurately map sites that drive transient oligomerization of intrinsically disordered proteins (IDP), such as A β, revealing how such IDP sites are affected by self-association inhibitors.
This project will expand spectroscopic in vitro studies with parallel investigations on cellular and animal model systems of neurodegeneration. Translation of atomistic models of ATP-A β interactions will potentially develop into novel methods for early AD diagnosis through efficient screening for new A β self-association inhibitors, which will serve as leads for AD therapies.