Abstract

Neuritic plaques, a pathological hallmark in Alzheimer’s disease (AD) brains, comprise extracellular aggregates of amyloid-beta (Aβ) peptide and degenerating neurites that accumulate autolysosomes. We found that, in the brains of patients with AD and in AD mouse models, Aβ plaque-associated Olig2- and NG2-expressing oligodendrocyte progenitor cells (OPCs), but not astrocytes, microglia, or oligodendrocytes, exhibit a senescence-like phenotype characterized by the upregulation of p21/CDKN1A, p16/INK4/CDKN2A proteins, and senescence-associated β-galactosidase activity. Molecular interrogation of the Aβ plaque environment revealed elevated levels of transcripts encoding proteins involved in OPC function, replicative senescence, and inflammation. Direct exposure of cultured OPCs to aggregating Aβ triggered cell senescence. Senolytic treatment of AD mice selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened Aβ load, and ameliorated cognitive deficits. Our findings suggest a role for Aβ-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments.

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Data availability

The data used to generate the figures in this study are available from the corresponding authors upon reasonable request.

Additional information

Journal peer review information: Nature Neuroscience thanks Valery Krizhanovsky and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Acknowledgements

We thank N. Sah, J. Tian, and R. Munk for technical support. We thank D. Baker at the Mayo Clinic for his valuable advice about the use of senolytic agents in vivo. This research was supported by the Intramural Research Programs of the National Institute on Aging (NIA) and the National Institute on Drug Abuse, and by an NIA grant supporting the University of Kentucky Alzheimer’s Disease Research Center (no. P30-AG0-28383).

Author information

Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD, USA

    • Peisu Zhang
    • , Yuki Kishimoto
    • , Roy G. Cutler
    •  & Mark P. Mattson
  2. Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD, USA

    • Ioannis Grammatikakis
    • , Kotb Abdelmohsen
    •  & Myriam Gorospe
  3. Laboratory of Clinical Investigation, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD, USA

    • Kamalvishnu Gottimukkala
    •  & Jyoti Misra Sen
  4. Electron Microscopy Core, National Institute on Drug Abuse Intramural Research Program, NIH, Baltimore, MD, USA

    • Shiliang Zhang
  5. Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, NIH, Baltimore, MD, USA

    • Vilhelm A. Bohr
  6. Immunology Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Jyoti Misra Sen
  7. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Mark P. Mattson

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Contributions

P.Z. designed and performed the experiments, analyzed the data, and wrote the manuscript. Y.K. performed the experiments and analyzed the data. I.G., K.A., S.Z., R.G.C., and J.T. generated the data. K.G. and J.M.S. generated and characterized the p16-ZsGreen reporter and the APP/PS1 and p16-ZsGreen reporter mice. M.P.M., M.G., and V.A.B. contributed to the experimental design and writing of the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Peisu Zhang or Mark P. Mattson.

Supplementary information

  1. Supplementary Figs. 1–21 and Supplementary Tables 1 & 2.

  2. Reporting Summary

  3. Supplementary Video 1

    Spatial relationship between senescent cells and Aβ plaques. p16 mRNA is shown in green, Aβ immunoreactivity in red and cell nuclei in blue (DAPI).

  4. Supplementary Video 2

    Spatial relationship between senescent cells and Aβ plaques. p16 mRNA is shown in green and LAMP1 protein immunoreactivity in pink.

  5. Supplementary Video 3

    Spatial relationship between senescent cells and Aβ plaques. p16 mRNA is shown in green, LAMP1 protein immunoreactivity in cyan and Aβ immunoreactivity in red.

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DOI

https://doi.org/10.1038/s41593-019-0372-9

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