Investigating gamma-secretase in human neurons reveals connections between cholesterol metabolism and synaptic function
Abstract/Contents
- Abstract
- Alzheimer's Disease (AD) is characterized by memory loss and dementia, with underlying synapse loss and synaptic dysfunction. While the strongest risk gene for late-onset AD is APOE, early-onset forms of AD are mainly caused by familial mutations of presenilins, the catalytic subunit of the protease gamma-secretase. Mutations in gamma-secretase are thought to cleave the amyloid precursor protein (APP), leading to toxic Aβ oligomers associated with synapse loss. However, evidence from non-neuronal cells and murine models suggests that gamma-secretase may cleave over 90 transmembrane proteins, including synaptic signaling, scaffolding, and adhesion proteins. The resulting intracellular fragments following cleavage can exert transcriptional control in the nucleus. We hypothesized that gamma-secretase plays an important role in regulating synaptic function. In this study, we address the current knowledge gap on the physiological role of gamma-secretase in maintaining the proper functioning of human synapses. Here, we show an unexpected role of cholesterol metabolism in the regulation of synaptic function by gamma-secretase. Using patch-clamp electrophysiology, we demonstrate that gamma-secretase is required for presynaptic release and postsynaptic response in human induced neurons (iN). With RNA-seq and qPCR, we find that gamma-secretase modulates cholesterol synthesis gene expression and immediate early gene expression. Total cholesterol levels were reduced in human iN following gamma-secretase inhibition, when measured by confocal imaging and spectroscopy. Treatment of human iN with statins revealed novel insight on pre- and postsynaptic function regulated by cellular cholesterol levels. Our data shows, for the first time, a connection between cholesterol metabolism and synaptic function that is modulated by gamma-secretase activity in human excitatory neurons. These findings provide insight into the effects of proteolytic cleavage by gamma-secretase on the synapse. Our work highlights the need to further understand cholesterol metabolism pathways and synaptic dysfunction in early- and late-onset AD pathophysiology.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Essayan-Perez, Sofia |
|---|---|
| Degree supervisor | Südhof, Thomas C |
| Thesis advisor | Südhof, Thomas C |
| Thesis advisor | Chen, Lu, (Professor of neurosurgery) |
| Thesis advisor | Wernig, Marius |
| Thesis advisor | Wyss-Coray, Anton |
| Degree committee member | Chen, Lu, (Professor of neurosurgery) |
| Degree committee member | Wernig, Marius |
| Degree committee member | Wyss-Coray, Anton |
| Associated with | Stanford University, Neurosciences Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Sofia Essayan-Perez. |
|---|---|
| Note | Submitted to the Neurosciences Program. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/ng513ms2190 |
Access conditions
- Copyright
- © 2022 by Sofia Essayan-Perez
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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