Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model
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)
-
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.
-
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).
Reviewing Editor
- Jessica Young, Institute for Stem Cell and Regenerative Medicine (ISCRM, United States
Publication history
- Preprint posted: December 22, 2020 (view preprint)
- Received: December 22, 2020
- Accepted: March 17, 2022
- Accepted Manuscript published: March 21, 2022 (version 1)
- Version of Record published: May 20, 2022 (version 2)
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.
Metrics
-
- 937
- Page views
-
- 172
- Downloads
-
- 0
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
- Stem Cells and Regenerative Medicine
Fusing brain organoids with blood vessel organoids leads to the incorporation of non-neural endothelial cells and microglia into the brain organoids.
-
- Computational and Systems Biology
- Stem Cells and Regenerative Medicine
Induced differentiation is one of the most experience- and skill-dependent experimental processes in regenerative medicine, and establishing optimal conditions often takes years. We developed a robotic AI system with a batch Bayesian optimization algorithm that autonomously induces the differentiation of induced pluripotent stem cell-derived retinal pigment epithelial (iPSC-RPE) cells. From 200 million possible parameter combinations, the system performed cell culture in 143 different conditions in 111 days, resulting in 88% better iPSC-RPE production than that obtained by the pre-optimized culture in terms of the pigmentation scores. Our work demonstrates that the use of autonomous robotic AI systems drastically accelerates systematic and unbiased exploration of experimental search space, suggesting immense use in medicine and research.