Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model
- Stanford University, United States
- University of California, Irvine, United States
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 end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the BMP pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.'
Data availability
Datasets generated are available on Dryad Digital Repository (doi:10.5061/dryad.mpg4f4qz0 and doi.org/10.5061/dryad.vx0k6djtf)
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Single-Cell RNA-sequencing of neural precursor cells from an Alzheimer's mouse model, wild-type mice, and Alzheimer's mice rescued with Usp16 haploinsufficiencyDryad Digital Repository, doi:10.5061/dryad.mpg4f4qz0.
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Microarray analysis of subventricular zone, hippocampus, and cortex from an Alzheimer's mouse model, wild-type mice, and Alzheimer's mice rescued with Usp16 haploinsufficiencyDryad Digital Repository, doi:10.5061/dryad.vx0k6djtf.
Article and author information
Author details
Funding
California Institute of Regenerative Medicine (Graduate Student Fellowship)
- Elizabeth Y Chen
Chan Zucherberg Foundationg Biohub Initiative
- Elizabeth Y Chen
- Robert C Jones
- Sai Saroja Kolluru
- Stephen R Quake
NIH (1R01AG059712-01)
- Felicia Reinitz
- Elizabeth Y Chen
- Benedetta Nicolis di Robilant
- Jane Antony
- Neha Gubbi
- Dalong Qian
- Michael F Clarke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were housed in accordance with the guidelines of Institutional AnimalCare Use Committee. All animal procedures and behavioral studies involved in this manuscript are compliant to Stanford Administrative Panel on Laboratory Animal Care (APLAC) Protocol 10868 pre-approved by the Stanford Institutional Animal Care and Use Committee (IACUC).
Copyright
© 2022, Reinitz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model
eLife 11:e66037.
https://doi.org/10.7554/eLife.66037
Further reading
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- Developmental Biology
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In holothurians, the regenerative process following evisceration involves the development of a ‘rudiment’ or ‘anlage’ at the injured end of the mesentery. This regenerating anlage plays a pivotal role in the formation of a new intestine. Despite its significance, our understanding of the molecular characteristics inherent to the constituent cells of this structure has remained limited. To address this gap, we employed state-of-the-art scRNA-seq and hybridization chain reaction fluorescent in situ hybridization analyses to discern the distinct cellular populations associated with the regeneration anlage. Through this approach, we successfully identified 13 distinct cell clusters. Among these, two clusters exhibit characteristics consistent with putative mesenchymal cells, while another four show features akin to coelomocyte cell populations. The remaining seven cell clusters collectively form a large group encompassing the coelomic epithelium of the regenerating anlage and mesentery. Within this large group of clusters, we recognized previously documented cell populations such as muscle precursors, neuroepithelial cells, and actively proliferating cells. Strikingly, our analysis provides data for identifying at least four other cellular populations that we define as the precursor cells of the growing anlage. Consequently, our findings strengthen the hypothesis that the coelomic epithelium of the anlage is a pluripotent tissue that gives rise to diverse cell types of the regenerating intestinal organ. Moreover, our results provide the initial view into the transcriptomic analysis of cell populations responsible for the amazing regenerative capabilities of echinoderms.
