# Regulation of y-secretase activity by modulatory proteins

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $865,155

## Abstract

Mutations in presenilin-1 (PS1) or Presenilin-2 (PS-2), the catalytic subunit of γ-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 γ-secretase may play a causative role in the late-onset form of AD. Moreover, the pathological role of γ-
secretase in EOAD has not been fully elucidated. Only a small fraction of the γ-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 γ-secretase modulatory proteins (GSMPs) in the regulation of γ-secretase
and examine their function in AD. Here we propose to investigate how γ-secretase activity is activated by
cerebrovascular disease mediated hypoxia and γ-secretase activating protein (GSAP). We will elucidate the
molecular basis of GSAP in modulation of γ-secretase for the processing of APP and Notch1. We will determine
the underlying mechanism by which Hif1α activates γ-secretase. Lastly, we will investigate the mechanisms by
which GSAP- and Hif1α- regulate γ-secretase activity in AD mouse models. The long-term goals of this proposal
are to elucidate the mechanism of γ-secretase modulation and identify novel γ-secretase regulatory proteins as
well as assess their relevance to AD. Our studies focus on the molecular basis of γ-secretase modulation by
modulatory proteins and have potentially significant impacts on understanding the disease mechanism and
developing therapeutics.

## Key facts

- **NIH application ID:** 9856956
- **Project number:** 5R01AG061350-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** YUEMING LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $865,155
- **Award type:** 5
- **Project period:** 2019-02-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856956

## Citation

> US National Institutes of Health, RePORTER application 9856956, Regulation of y-secretase activity by modulatory proteins (5R01AG061350-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856956. Licensed CC0.

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