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Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.

Publication ,  Journal Article
Shi, Y; Manis, M; Long, J; Wang, K; Sullivan, PM; Remolina Serrano, J; Hoyle, R; Holtzman, DM
Published in: J Exp Med
November 4, 2019

Chronic activation of brain innate immunity is a prominent feature of Alzheimer's disease (AD) and primary tauopathies. However, to what degree innate immunity contributes to neurodegeneration as compared with pathological protein-induced neurotoxicity, and the requirement of a particular glial cell type in neurodegeneration, are still unclear. Here we demonstrate that microglia-mediated damage, rather than pathological tau-induced direct neurotoxicity, is the leading force driving neurodegeneration in a tauopathy mouse model. Importantly, the progression of ptau pathology is also driven by microglia. In addition, we found that APOE, the strongest genetic risk factor for AD, regulates neurodegeneration predominantly by modulating microglial activation, although a minor role of apoE in regulating ptau and insoluble tau formation independent of its immunomodulatory function was also identified. Our results suggest that therapeutic strategies targeting microglia may represent an effective approach to prevent disease progression in the setting of tauopathy.

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Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

November 4, 2019

Volume

216

Issue

11

Start / End Page

2546 / 2561

Location

United States

Related Subject Headings

  • tau Proteins
  • Tauopathies
  • Pyrroles
  • Neurodegenerative Diseases
  • Microglia
  • Mice, Transgenic
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Immunology
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Shi, Y., Manis, M., Long, J., Wang, K., Sullivan, P. M., Remolina Serrano, J., … Holtzman, D. M. (2019). Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med, 216(11), 2546–2561. https://doi.org/10.1084/jem.20190980
Shi, Yang, Melissa Manis, Justin Long, Kairuo Wang, Patrick M. Sullivan, Javier Remolina Serrano, Rosa Hoyle, and David M. Holtzman. “Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.J Exp Med 216, no. 11 (November 4, 2019): 2546–61. https://doi.org/10.1084/jem.20190980.
Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, et al. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546–61.
Shi, Yang, et al. “Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model.J Exp Med, vol. 216, no. 11, Nov. 2019, pp. 2546–61. Pubmed, doi:10.1084/jem.20190980.
Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546–2561.

Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

November 4, 2019

Volume

216

Issue

11

Start / End Page

2546 / 2561

Location

United States

Related Subject Headings

  • tau Proteins
  • Tauopathies
  • Pyrroles
  • Neurodegenerative Diseases
  • Microglia
  • Mice, Transgenic
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Immunology
  • Humans