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 to further optimize a unique set of small molecule drugs known as soluble gamma?secretase modulators (SGSMs) to further explore novel AD therapeutics. This proposal will focus on the medicinal chemistry lead optimization and the testing of the efficacy of these drugs aimed at halting A?42?related pathologies in AD transgenic mice. Our overarching hypothesis is SGSM 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 complete all of the necessary IND-enabling studies and to file an IND on a very potent and safe SGSM.

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 complete all of the necessary IND?enabling studies and to file an IND on a very potent and safe soluble gamma?secretase modulator (SGSM) for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AG048986-03S1
Application #
9583368
Study Section
Special Emphasis Panel (ZAG1)
Program Officer
Petanceska, Suzana
Project Start
2016-05-15
Project End
2019-04-30
Budget Start
2018-09-15
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093