Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model

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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Fig. 1: OPCs exhibiting a senescence phenotype are associated with Aβ plaques in brains of patients with AD.
Fig. 2: Association of cellular senescence and OPC markers with Aβ plaques in the brains of APP/PS1 double-mutant transgenic mice.
Fig. 3: Molecular and ultrastructural features of Aβ-associated OPC senescence.
Fig. 4: Senolytic treatment selectively kills p16- and p21-expressing OPCs from the Aβ plaque environment in AD mice.
Fig. 5: Long-term senolytic treatment prevents Aβ accumulation and hippocampus-dependent cognitive impairment in APP/PS1 AD mice.

Data availability

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

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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

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Authors

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.

Corresponding authors

Correspondence to Peisu Zhang or Mark P. Mattson.

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The authors declare no competing interests.

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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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Supplementary information

41593_2019_372_MOESM3_ESM.mp4

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

41593_2019_372_MOESM4_ESM.mp4

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

41593_2019_372_MOESM5_ESM.mp4

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

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

Reporting Summary

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).

Supplementary Video 2

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

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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Zhang, P., Kishimoto, Y., Grammatikakis, I. et al. Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22, 719–728 (2019). https://doi.org/10.1038/s41593-019-0372-9

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