Inhibiting the BMP pathway rescues neural stem cell defects in Alzheimer's disease
Abstract/Contents
- Abstract
- Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting later phenotypes including removing the plaques, tangles, or inflammation have limited efficacy. In a mouse model of AD harboring mutant amyloid precursor protein, we demonstrate that targeting an earlier phenotype, specifically impaired neural precursor cell (NPC) self-renewal, can reverse cognitive defects in AD. For the first time, we show this neural stem cell defect is cell intrinsic and occurs before the widespread inflammation and amyloid plaque pathology seen in AD, which may make it the earliest indicator of disease. To further query the mechanism of this self-renewal defect, we turn to single-cell RNA-sequencing of these neural precursor cell populations to show AD-enriched pathways that would be missed in bulk whole-brain RNA sequencing. Our analysis revealed BMP signaling as the only enriched pathway at this early phase that is consistently enriched with aging throughout the disease process. Genetic reduction of USP16, a critical physiological antagonist of self-renewal gene Bmi1, led to normalized BMP signaling, improved NPC self-renewal, and decreased Cdkn2a expression. While exploring later disease manifestations in AD, we found that the reduction in USP16 expression was sufficient to decrease astrogliosis in vivo and improve cognitive function. Hence, our data reveal USP16 as a novel therapeutic target that rescues neural precursor cell function in AD models prior to the onset of downstream pathology. This rescue occurs through repression of Cdkn2a and BMP signaling and may present a novel alternative therapy to drugs targeting plaques or inflammation.
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 | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Chen, Elizabeth Yang |
|---|---|
| Degree supervisor | Clarke, Michael F |
| Thesis advisor | Clarke, Michael F |
| Thesis advisor | Heller, H. Craig |
| Thesis advisor | Palmer, Theo |
| Degree committee member | Heller, H. Craig |
| Degree committee member | Palmer, Theo |
| Associated with | Stanford University, Department of Stem Cell Biology and Regenerative Medicine. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Elizabeth Chen. |
|---|---|
| Note | Submitted to the Department of Stem Cell Biology and Regenerative Medicine. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Elizabeth Yang Chen
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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