# Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $762,972

## Abstract

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the United States that affects more
than 5 million Americans. Synapses are the earliest affected component of the brain during AD pathogenesis,
suggesting that the cognitive decline and neuronal loss in AD initiates with synaptic dysfunction. Despite much
effort, however, no definitive understanding of AD pathogenesis is available, and no therapies that alleviate or
even stop progression of AD are known. Genetic studies identified rare mutations in presenilin and in APP genes
that cause early-onset familial AD (FAD), and described common variants in several genes, chiefly the ApoE
and TREM2 genes, that predispose to sporadic AD, providing potential clues to AD pathogenesis. Presenilin
mutations impair the activity of γ-secretase, an intramembranous protease that cleaves a large number of
membrane proteins, including APP. Presenilin and APP mutations associated with FAD both enhance production
of Aβ, a cleavage product of APP. Moreover, all AD patients suffer from an accumulation of Aβ in brain, leading
to the `amyloid Aβ hypothesis' whereby AD is induced by Aβ amyloid accumulation in brain. However, therapies
that prevent or even reverse Aβ accumulation in brain have not been effective in treating AD. Furthermore, ApoE
and TREM2 are not directly related to Aβ, but seem to influence microglial function, inflammatory responses,
and/or lipid metabolism. Indeed, alterations in lipid content are a prominent feature of AD brains, suggesting that
Aβ may be related to AD pathogenesis in a manner that is not related to amyloid formation. Indeed, in preliminary
experiments we observed that a chronic decrease γ-secretase activity, as would be observed with FAD-
associated mutations of presenilin genes, causes a major decrease in synaptic transmission and an upregulation
of cholesterol synthesis. Based on the all of these findings together, we here propose an interdisciplinary project
that examines the role of changes in γ-secretase activity in synaptic function and lipid metabolism as a potential
pathogenetic mechanism in AD. We describe four specific aims that will investigate the relationship of γ-
secretase to synaptic transmission, the mechanism by which γ-secretase activity normally suppresses
cholesterol synthesis, and the possibility that increased cholesterol synthesis induced by a chronic decrease in
γ-secretase activity is responsible for the observed synaptic impairments. Moreover, the proposed specific aims
will explore the possibility that ApoE4, the ApoE variant predisposing to AD, also acts by altering lipid metabolism
in neurons. These experiments will adopt a multidisciplinary approach that will be carried out in human neurons
and in mouse brains, and will combine cell biology, transcriptomics, CRISPR, and electrophysiology techniques
to explore the underlying mechanisms. Among others, these experiments will contribute to our understanding of
how presenilin mutations ...

## Key facts

- **NIH application ID:** 10839810
- **Project number:** 5R01AG070919-04
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Thomas C. Sudhof
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $762,972
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839810

## Citation

> US National Institutes of Health, RePORTER application 10839810, Regulation of cholesterol by y-secretase and ApoE: Implications for AD pathogenesis and synaptic function (5R01AG070919-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10839810. Licensed CC0.

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