Neuron
Volume 109, Issue 8, 21 April 2021, Pages 1283-1301.e6
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Article
Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

https://doi.org/10.1016/j.neuron.2021.02.010Get rights and content
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Highlights

  • β-amyloid pathology accelerates tau accumulation and tau-mediated neurodegeneration

  • Trem2 enables strong microglial response in mice with both amyloid and tau pathologies

  • Deleting Trem2 intensifies tau pathology and brain atrophy only if β-amyloid is present

  • TREM2 function may be protective at all stages of Alzheimer’s disease pathogenesis

Summary

Loss-of-function TREM2 mutations strongly increase Alzheimer’s disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2 deficiency in the pR5-183 mouse model expressing mutant tau alone or in TauPS2APP mice, in which β-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was amyloid-dependent and Trem2-dependent. In the presence of β-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without β-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau.

Keywords

Alzheimer’s disease
TREM2
microglia
tauopathy
neurodegeneration
gliosis
neuroinflammation
single-cell RNA sequencing
MRI
disease-associated microglia

Cited by (0)

5

Present address: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA

6

Present address: Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, USA

7

These authors contributed equally

8

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