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Single-cell RNA-Seq of TauP301L, PS2APP/TauP301L, and PS2APP/TauP301L/TREM2KO mouse hippocampi, 19-22 months old

ABSTRACT: Loss-of-function mutations in TREM2 (triggering receptor expressed on myeloid cells 2) strongly increase Alzheimer’s disease (AD) risk. Preclinical models using Trem2 deletion or overexpression have revealed a protective Trem2 function related to β-amyloid accumulation, a process that is most prominent during the pre-diagnosis stages of AD. The role of TREM2 in later AD stages characterized by tau-mediated neurodegeneration is less clear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2-deficient mice expressing mutant tau alone (pR5-183 model) or in the TauPS2APP model, 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 both 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

ORGANISM(S): Mus musculus

PROVIDER: GSE153895 | GEO | 2021/02/24

REPOSITORIES: GEO

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