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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Shi, Y; Manis, M; Long, J; Wang, K; Sullivan, PM; Remolina Serrano, J; Hoyle, R; Holtzman, DM

Published Date

  • November 4, 2019

Published In

Volume / Issue

  • 216 / 11

Start / End Page

  • 2546 - 2561

PubMed ID

  • 31601677

Pubmed Central ID

  • PMC6829593

Electronic International Standard Serial Number (EISSN)

  • 1540-9538

Digital Object Identifier (DOI)

  • 10.1084/jem.20190980


  • eng

Conference Location

  • United States