Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain

Nicole Maphis, Guixiang Xu, Olga N. Kokiko-Cochran, Shanya Jiang, Astrid Cardona, Richard M. Ransohoff, Bruce Lamb, Kiran Bhaskar

Research output: Contribution to journalArticle

145 Citations (Scopus)

Abstract

Pathological aggregation of tau is a hallmark of Alzheimer's disease and related tauopathies. We have previously shown that the deficiency of the microglial fractalkine receptor (CX3CR1) led to the acceleration of tau pathology and memory impairment in an hTau mouse model of tauopathy. Here, we show that microglia drive tau pathology in a cell-autonomous manner. First, tau hyperphosphorylation and aggregation occur as early as 2 months of age in hTauCx3cr1(-/-) mice. Second, CD45(+) microglial activation correlates with the spatial memory deficit and spread of tau pathology in the anatomically connected regions of the hippocampus. Third, adoptive transfer of purified microglia derived from hTauCx3cr1(-/-) mice induces tau hyperphosphorylation within the brains of non-transgenic recipient mice. Finally, inclusion of interleukin 1 receptor antagonist (Kineret®) in the adoptive transfer inoculum significantly reduces microglia-induced tau pathology. Together, our results suggest that reactive microglia are sufficient to drive tau pathology and correlate with the spread of pathological tau in the brain.

Original languageEnglish (US)
Pages (from-to)1738-1755
Number of pages18
JournalBrain
Volume138
DOIs
StatePublished - Jun 1 2015
Externally publishedYes

Fingerprint

Microglia
Pathology
Tauopathies
Brain
Adoptive Transfer
Interleukin 1 Receptor Antagonist Protein
Interleukin-1 Receptors
Memory Disorders
Hippocampus
Alzheimer Disease
Drive

Keywords

  • Alzheimer’s disease
  • microglia
  • neuroinflammation
  • tau protein
  • tauopathies

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Maphis, N., Xu, G., Kokiko-Cochran, O. N., Jiang, S., Cardona, A., Ransohoff, R. M., ... Bhaskar, K. (2015). Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain, 138, 1738-1755. https://doi.org/10.1093/brain/awv081

Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. / Maphis, Nicole; Xu, Guixiang; Kokiko-Cochran, Olga N.; Jiang, Shanya; Cardona, Astrid; Ransohoff, Richard M.; Lamb, Bruce; Bhaskar, Kiran.

In: Brain, Vol. 138, 01.06.2015, p. 1738-1755.

Research output: Contribution to journalArticle

Maphis, N, Xu, G, Kokiko-Cochran, ON, Jiang, S, Cardona, A, Ransohoff, RM, Lamb, B & Bhaskar, K 2015, 'Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain', Brain, vol. 138, pp. 1738-1755. https://doi.org/10.1093/brain/awv081
Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain. 2015 Jun 1;138:1738-1755. https://doi.org/10.1093/brain/awv081
Maphis, Nicole ; Xu, Guixiang ; Kokiko-Cochran, Olga N. ; Jiang, Shanya ; Cardona, Astrid ; Ransohoff, Richard M. ; Lamb, Bruce ; Bhaskar, Kiran. / Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. In: Brain. 2015 ; Vol. 138. pp. 1738-1755.
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