# The Role of Gamma-Secretase in Human Neuronal Physiology

> **NIH NIH F30** · STANFORD UNIVERSITY · 2021 · $25,238

## Abstract

Abstract
Alzheimer's Disease (AD) is the leading cause of dementia in the United States, affecting 5.7 million Americans,
yet no treatments exist. Early-onset AD is most commonly caused by familial mutations of presenilins, the
catalytic subunit of the protease g-secretase. Mutated 𝛾-secretase cleaves the amyloid precursor protein (APP)
and releases toxic b-amyloid peptides associated with synapse loss. However, 𝛾-secretase may also contribute
to synaptic dysfunction in AD through mechanisms beyond APP processing. While 𝛾-secretase contributes to
AD pathology, its broader physiological roles in maintaining the proper functioning of human synapses is poorly
understood. Evidence from non-neuronal cells and murine models suggest that 𝛾-secretase may process over
90 transmembrane proteins, including synaptic signaling, scaffolding, and adhesion proteins. A knowledge gap
exists on how 𝛾-secretase maintains the proper functioning of healthy synapses in human neurons, which can
further inform pathoetiologies of AD.
The overall objective of this proposal is to examine in human neurons how 𝛾-secretase regulates biochemical,
morphological, and functional features of synapses, with and without chronic activity modulation. Preliminary
work in human neurons validates that 𝛾-secretase is required for b-amyloid production and cleavage of full-length
APP and Neurexin (Nrxn) proteins. Early results show that 𝛾-secretase is necessary for regulating key
presynaptic and postsynaptic protein levels, as well as the number of synapses.
Aim 1 will characterize the role of 𝛾-secretase in regulating neuronal protein composition, synapse formation,
and synaptic transmission to better understand its functions at human synapses. We hypothesize that 𝛾-
secretase is needed for maintaining synaptic integrity, through the processing of presynaptic and postsynaptic
proteins. Aim 2 will determine how 𝛾-secretase modulates synapses in response to chronic increases or
decreases of neural activity. As other proteases have activity-dependent regulation, we hypothesize that 𝛾-
secretase regulates synaptic protein composition and synaptic transmission following chronic modulation.
Understanding the role of 𝛾-secretase at healthy synapses will provide insight into the physiological synaptic
processes regulated by this protease, which will advance our understanding of the normal aging brain and AD
pathology. The proposed project will establish the neuronal roles of 𝛾-secretase in a human neuron-specific
manner. Further, it will reveal the function of 𝛾-secretase in modulating synaptic activity. Greater insight into
proteolytic activity in human neurons will elucidate candidate pathways and potential therapeutic targets for AD.

## Key facts

- **NIH application ID:** 10222551
- **Project number:** 5F30AG064819-03
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Sofia Essayan-Perez
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $25,238
- **Award type:** 5
- **Project period:** 2019-09-16 → 2022-03-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222551

## Citation

> US National Institutes of Health, RePORTER application 10222551, The Role of Gamma-Secretase in Human Neuronal Physiology (5F30AG064819-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10222551. Licensed CC0.

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