Mutations in presenilin-1 (PS1) or Presenilin-2 (PS-2), the catalytic subunit of ?-secretase, lead to the early- onset form of Alzheimer?s disease (EOAD). However, the causes of late-onset AD (LOAD) are under active investigation. The pathological features and functional connectivity of both forms of AD are similar, suggesting that ?-secretase may play a causative role in the late-onset form of AD. Moreover, the pathological role of ?- secretase in EOAD has not been fully elucidated. Only a small fraction of the ?-secretase complex is catalytically active and the function and activation of the inactive complex is unknown. The objectives of this proposal are to elucidate the mechanism of action of ?-secretase modulatory proteins (GSMPs) in the regulation of ?-secretase and examine their function in AD. Here we propose to investigate how ?-secretase activity is activated by cerebrovascular disease mediated hypoxia and ?-secretase activating protein (GSAP). We will elucidate the molecular basis of GSAP in modulation of ?-secretase for the processing of APP and Notch1. We will determine the underlying mechanism by which Hif1? activates ?-secretase. Lastly, we will investigate the mechanisms by which GSAP- and Hif1?- regulate ?-secretase activity in AD mouse models. The long-term goals of this proposal are to elucidate the mechanism of ?-secretase modulation and identify novel ?-secretase regulatory proteins as well as assess their relevance to AD. Our studies focus on the molecular basis of ?-secretase modulation by modulatory proteins and have potentially significant impacts on understanding the disease mechanism and developing therapeutics.

Public Health Relevance

Abnormal ?-secretase activity causes the early-onset form of Alzheimer?s disease (AD). This proposal investigates the mechanism of ?-secretase activation under pathophysiological conditions that increase risk for AD. This application addresses unmet needs in AD research with clear mechanistic insights and translational potentials.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG061350-02
Application #
9856956
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2019-02-01
Project End
2023-11-30
Budget Start
2019-12-15
Budget End
2020-11-30
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065