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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Wyss-Coray, T. Inflammation in Alzheimer disease: driving force, bystander or beneficial response? Nat. Med. 12, 1005–1015 (2006).

  2. 2.

    Nixon, R. A. The role of autophagy in neurodegenerative disease. Nat. Med. 19, 983–997 (2013).

  3. 3.

    Scheltens, P. et al. Alzheimer’s disease. Lancet 388, 505–517 (2016).

  4. 4.

    Malm, T. M., Jay, T. R. & Landreth, G. E. The evolving biology of microglia in Alzheimer’s disease. Neurotherapeutics 12, 81–93 (2015).

  5. 5.

    Muñoz-Espín, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).

  6. 6.

    Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011).

  7. 7.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

  8. 8.

    Baker, D. J. et al. Naturally occurringp16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

  9. 9.

    Childs, B. G. et al. Senescent intimal foam cells are deleterious at all stages of atherosclerosis. Science 354, 472–477 (2016).

  10. 10.

    Xu, M. et al. Senolytics improve physical function and increase lifespan in old age. Nat. Med. 24, 1246–1256 (2018).

  11. 11.

    Bussian, T. J. et al. Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562, 578–582 (2018).

  12. 12.

    Musi, N. et al. Tau protein aggregation is associated with cellular senescence in the brain. Aging Cell 17, e12840 (2018).

  13. 13.

    Geha, S. et al. NG2+/Olig2+ cells are the major cycle-related cell population of the adult human normal brain. Brain Pathol. 20, 399–411 (2010).

  14. 14.

    Kang, S. H., Fukaya, M., Yang, J. K., Rothstein, J. D. & Bergles, D. E. NG2+CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration. Neuron 68, 668–681 (2010).

  15. 15.

    Clemente, D., Ortega, M. C., Melero-Jerez, C. & de Castro, F. The effect of glia-glia interactions on oligodendrocyte precursor cell biology during development and in demyelinating diseases. Front. Cell. Neurosci. 7, 268 (2013).

  16. 16.

    Jennings, A. R. & Carroll, W. M. Oligodendrocyte lineage cells in chronic demyelination of multiple sclerosis optic nerve. Brain Pathol. 25, 517–530 (2015).

  17. 17.

    Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

  18. 18.

    Kurz, D. J., Decary, S., Hong, Y. & Erusalimsky, J. D. Senescence-associated (beta)-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J. Cell Sci. 113, 3613–3622 (2000).

  19. 19.

    Debacq-Chainiaux, F., Erusalimsky, J. D., Campisi, J. & Toussaint, O. Protocols to detect senescence-associated beta-galactosidase (SA-betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat. Protoc. 4, 1798–1806 (2009).

  20. 20.

    Borchelt, D. R. et al. Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19, 939–945 (1997).

  21. 21.

    Piechota, M. et al. Is senescence-associated β-galactosidase a marker of neuronal senescence? Oncotarget 7, 81099–81109 (2016).

  22. 22.

    Zhan, X. et al. Myelin basic protein associates with AβPP, Aβ1–42, and amyloid plaques in cortex of Alzheimer’s disease brain. J. Alzheimers Dis. 44, 1213–1229 (2015).

  23. 23.

    Jiang, P. et al. Generation and characterization of spiking and nonspiking oligodendroglial progenitor cells from embryonic stem cells. Stem Cells 31, 2620–2631 (2013).

  24. 24.

    Meijer, D. H. et al. Separated at birth? The functional and molecular divergence of OLIG1 and OLIG2. Nat. Rev. Neurosci. 13, 819–831 (2012).

  25. 25.

    Condello, C., Yuan, P., Schain, A. & Grutzendler, J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun. 6, 6176 (2015).

  26. 26.

    Gowrishankar, S. et al. Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques. Proc. Natl Acad. Sci. USA 112, E3699–E3708 (2015).

  27. 27.

    Barrachina, M., Maes, T., Buesa, C. & Ferrer, I. Lysosome-associated membrane protein 1 (LAMP-1) in Alzheimer’s disease. Neuropathol. Appl. Neurobiol. 32, 505–516 (2006).

  28. 28.

    Nixon, R. A. et al. Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study. J. Neuropathol. Exp. Neurol. 64, 113–122 (2005).

  29. 29.

    Zhu, Y. et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14, 644–658 (2015).

  30. 30.

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

  31. 31.

    Bhat, R. et al. Astrocyte senescence as a component of Alzheimer’s disease. PLoS One 7, e45069 (2012).

  32. 32.

    Rademakers, R., Neumann, M. & Mackenzie, I. R. Advances in understanding the molecular basis of frontotemporal dementia. Nat. Rev. Neurol. 8, 423–434 (2012).

  33. 33.

    LeBrasseur, N. K., Tchkonia, T. & Kirkland, J. L. Cellular senescence and the biology of aging, disease, and frailty. Nestle Nutr. Inst. Workshop Ser. 83, 11–18 (2015).

  34. 34.

    Baker, D. J. & Petersen, R. C. Cellular senescence in brain aging and neurodegenerative diseases: evidence and perspectives. J. Clin. Invest. 128, 1208–1216 (2018).

  35. 35.

    Neumann, B. & Kazanis, I. Oligodendrocyte progenitor cells: the ever mitotic cells of the CNS. Front. Biosci. (Schol. Ed.) 8, 29–43 (2016).

  36. 36.

    Zhang, R., Chopp, M. & Zhang, Z. G. Oligodendrogenesis after cerebral ischemia. Front. Cell. Neurosci. 7, 201 (2013).

  37. 37.

    Antel, J. P. et al. Immunology of oligodendrocyte precursor cells in vivo and in vitro. J. Neuroimmunol. https://doi.org/10.1016/j.jneuroim.2018.03.006 (2018).

  38. 38.

    Chinta, S. J. et al. Cellular senescence is induced by the environmental neurotoxin paraquat and contributes to neuropathology linked to Parkinson’s disease. Cell Rep. 22, 930–940 (2018).

  39. 39.

    Mattson, M. P. Pathways towards and away from Alzheimer’s disease. Nature 430, 631–639 (2004).

  40. 40.

    Salter, M. W. & Stevens, B. Microglia emerge as central players in brain disease. Nat. Med. 23, 1018–1027 (2017).

  41. 41.

    Yang, L. L. et al. Pharmacokinetic comparison between quercetin and quercetin 3-O-β-glucuronide in rats by UHPLC-MS/MS. Sci. Rep. 6, 35460 (2016).

  42. 42.

    Zhang, S. et al. Dopaminergic and glutamatergic microdomains in a subset of rodent mesoaccumbens axons. Nat. Neurosci. 18, 386–392 (2015).

  43. 43.

    Zhang, P. et al. Novel RNA- and FMRP-binding protein TRF2-S regulates axonal mRNA transport and presynaptic plasticity. Nat. Commun. 6, 8888 (2015).

  44. 44.

    Stine, W. B. Jr., Dahlgren, K. N., Krafft, G. A. & LaDu, M. J. In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J. Biol. Chem. 278, 11612–11622 (2003).

  45. 45.

    Faucher, P., Mons, N., Micheau, J., Louis, C. & Beracochea, D. J. Hippocampal injections of oligomeric amyloid β-peptide (1–42) induce selective working memory deficits and long-lasting alterations of ERK signaling pathway. Front. Aging Neurosci. 7, 245 (2016).

  46. 46.

    Kashiwaya, Y. et al. A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease. Neurobiol. Aging 34, 1530–1539 (2013).

  47. 47.

    Sykora, P. et al. DNA polymerase β deficiency leads to neurodegeneration and exacerbates Alzheimer disease phenotypes. Nucleic Acids Res. 43, 943–959 (2015).

Download references


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


  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


  1. Search for Peisu Zhang in:

  2. Search for Yuki Kishimoto in:

  3. Search for Ioannis Grammatikakis in:

  4. Search for Kamalvishnu Gottimukkala in:

  5. Search for Roy G. Cutler in:

  6. Search for Shiliang Zhang in:

  7. Search for Kotb Abdelmohsen in:

  8. Search for Vilhelm A. Bohr in:

  9. Search for Jyoti Misra Sen in:

  10. Search for Myriam Gorospe in:

  11. Search for Mark P. Mattson in:


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.

About this article

Publication history






Further reading