Alzheimer?s disease (AD) is defined neuropathologically by extracellular plaques composed of ?-amyloid (A?42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. A? accumulation and hyperphosphorylation of tau are recognized as key events leading to full blown AD neuropathology. Here we propose comprehensive in vitro analysis of a unique set of novel small molecule drugs known gamma- secretase modulators (GSMs) to further explore AD therapeutics. This proposal will focus on testing an optimal lead clinical candidate for efficacy in human neurons aimed at halting A?42- related pathologies AD. Our overarching hypothesis is GSM therapy aimed to disrupt production of A?42 will be an efficacious treatment approach for prodromal or early AD, as well as sporadic late-onset AD. The goal of this project is to validate target engagement in human neurons from selected patients.

Public Health Relevance

Alzheimer?s disease (AD) is defined neuropathologically by extracellular plaques composed of ?-amyloid (A?42) and intracellular tangles consisting of hyperphosphorylated forms of the microtubule-associated protein tau. A? accumulation and hyperphosphorylation of tau are recognized as key events leading to full-blown AD neuropathology. The ultimate goal of this project is to test in human neurons a very potent and safe gamma-secretase modulator (GSM) for Alzheimer?s disease treatment.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01RX002259-02
Application #
9501564
Study Section
Blank (RRD6)
Project Start
2017-06-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA San Diego Healthcare System
Department
Type
DUNS #
073358855
City
San Diego
State
CA
Country
United States
Zip Code
92161