Molecular Intermediates and Regulation of the Abeta-Tau Pathogenic Cascade

James A. Haley Va Medical Center, Tampa FL

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): As the major defining characteristic of Alzheimer's disease (AD) brains is the excessive accumulation of toxic proteins called A?nd Tau, understanding the biological mechanisms by which A?onnects to tau dysfunction are critical for designing effective therapeutic treatments for AD. A?s generated from two cuts made by molecular scissors (named ?and ?-secretases) in its parent protein, APP, while Tau's main function is to stabilize microtubules. We found 4 major proteins (?integrin, RanBP9, Cofilin, & SSH1) in a pathway that not only promotes Aproduction but also relays the neurotoxic signals induced by A?o Tau, thereby promoting both pathologies. Inhibiting any one of these proteins could potentially stop the progression of AD, and as such, represent attractive and viable therapeutic targets. We have developed chemicals that inhibit one of these proteins (SSH1), the first ones ever characterized in academia or industry, and they show effectiveness not only in reducing A?roduction but also antagonizing A?nduced neurotoxicity and Tau dysfunction in nerve cells. By utilizing molecular, biochemical, cell biological, electrophysiological, and behavioral tools, we propose to 1) further characterize this pathway as intermediates between A?nd Tau pathologies in mouse models of Tau pathology and 2) better understand the physical and functional role of the RanBP9-SSH1-Cofilin pathway as critical nodes for bidirectional neurotoxic signaling between A?nd Tau pathologies in primary neurons, transfected cells, in the test tube, and in autopsied human brains.