Understanding the Inhibition of Age-Induced Neurotoxic Ab-Oligomers

Age is a major risk factor for Alzheimer’s Disease (AD). While no cure is currently available for AD, hope for potential AD therapies
comes from recent clinical trials showing that suppressing soluble oligomers formed by an endogenous peptide called Ab
significantly slows AD progression. However, current methods to target Ab oligomers rely on antibodies that lead to severe side
effects, including possibly fatal brain bleeding. Hence, it is critical to find alternative approaches to safely decrease toxic Ab
oligomers built up during aging. Aging significantly reduces the levels of ATP, which has recently been shown to function as
hydrotrope, i.e. an effective molecular chaperone that prevents Ab self-association. Yet, the mechanism underlying this new ATP
function is currently unknown because of the inherently transient nature of the elusive Ab oligomers. To address this experimental
challenge, the Melacini group has recently developed spectroscopic methods aimed at accurately mapping the sites that drive
transient oligomerization of intrinsically disordered proteins (IDP), such as Ab, and at revealing how such IDP sites are affected by
self-association inhibitors. The goal of the proposed project is to dissect the mechanism of action of ATP and other nucleotides as
Ab oligomerization inhibitors by using these methods. The researchers will collaborate with colleagues in the Faculty of Health Sciences to
complement their spectroscopic in vitro studies on the effect of nucleotides on Ab oligomerization with parallel investigations on
cellular and animal (neumatode C. Elegans and mouse) model systems of neurodegeneration. The researchers will also collaborate with
colleagues in Engineering to translate their atomistic models of ATP-Ab interactions into novel methods for early AD diagnosis and
for efficiently screening for new Ab self-association inhibitors, which will serve as leads for AD therapies. The research team anticipates that the
proposed project is relevant to understanding how AD can be detected early and treated effectively.