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)

The following data sets were generated

Article and author information

Author details

  1. Felicia Reinitz

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    Felicia Reinitz, filer of a provisional patent: U.S.Provisional Application No. 63/124,644 titled Modulating BMP signaling in the treatment of Alzheimer's disease".".
  2. Elizabeth Y Chen

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    Elizabeth Y Chen, filer of a provisional patent: U.S.Provisional Application No. 63/124,644 titled Modulating BMP signaling in the treatment of Alzheimer's disease".".
  3. Benedetta Nicolis di Robilant

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    Benedetta Nicolis di Robilant, is the co-founder of Dorian Therapeutics. Dorian therapeutics was incorporated in June 2018 and it is an early stage anti-aging company that focuses on the process of cellular senescence. Most of the experiments were performed before the company was formed..
  4. Bayarsaikhan Chuluun

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  5. Jane Antony

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    Jane Antony, filer of a provisional patent: U.S.Provisional Application No. 63/124,644 titled Modulating BMP signaling in the treatment of Alzheimer's disease".".
  6. Robert C Jones

    Department of Bioengineering, Stanford University, Stanford, United States
    Competing interests
    Robert C Jones, filer of a provisional patent: U.S.Provisional Application No. 63/124,644 titled Modulating BMP signaling in the treatment of Alzheimer's disease".".
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7235-9854
  7. Neha Gubbi

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  8. Karen Lee

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  9. William Hai Dang Ho

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  10. Sai Saroja Kolluru

    Department of Bioengineering, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  11. Dalong Qian

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  12. Maddalena Adorno

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    Maddalena Adorno, is the co-founder of Dorian Therapeutics. Dorian therapeutics was incorporated in June 2018 and it is an early stage anti-aging company that focuses on the process of cellular senescence. Most of the experiments were performed before the company was formed..
  13. Katja Piltti

    Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
  14. Aileen Anderson

    Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8203-8891
  15. Michelle Monje

    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3547-237X
  16. H Craig Heller

    Department of Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4479-5880
  17. Stephen R Quake

    Department of Bioengineering, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1613-0809
  18. Michael F Clarke

    Department of Bioengineering, Stanford University, Stanford, United States
    For correspondence
    mfclarke@stanford.edu
    Competing interests
    Michael F Clarke, filer of a provisional patent: U.S.Provisional Application No. 63/124,644 titled Modulating BMP signaling in the treatment of Alzheimer's disease".".
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6889-4926

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

  1. Jessica Young, Institute for Stem Cell and Regenerative Medicine (ISCRM, United States

Publication history

  1. Preprint posted: December 22, 2020 (view preprint)
  2. Received: December 22, 2020
  3. Accepted: March 17, 2022
  4. Accepted Manuscript published: March 21, 2022 (version 1)
  5. 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.

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  1. Felicia Reinitz
  2. Elizabeth Y Chen
  3. Benedetta Nicolis di Robilant
  4. Bayarsaikhan Chuluun
  5. Jane Antony
  6. Robert C Jones
  7. Neha Gubbi
  8. Karen Lee
  9. William Hai Dang Ho
  10. Sai Saroja Kolluru
  11. Dalong Qian
  12. Maddalena Adorno
  13. Katja Piltti
  14. Aileen Anderson
  15. Michelle Monje
  16. H Craig Heller
  17. Stephen R Quake
  18. Michael F Clarke
(2022)
Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model
eLife 11:e66037.
https://doi.org/10.7554/eLife.66037

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