Single-cell RNA-Seq of TauP301L, PS2APP/TauP301L, and PS2APP/TauP301L/TREM2KO mouse hippocampi, 19-22 months old
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 ß-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 ß-amyloid and tau pathologies, we examined Trem2-deficient mice expressing mutant tau alone (pR5-183 model) or in the TauPS2APP model, in which ß-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 ß-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without ß-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 ß-amyloid facilitates the spreading of pathogenic tau Overall design: RNA isolated from sorted hippocampi from male non-transgenic (n=2), Trem2ko (n=1), P301Lhomo (n=3), TauPS2APP (n=3), and TauPS2APP;Trem2ko (n=3) mice. All mice were 19-22 months at the time of perfusion. Following the manuscript, the one Trem2ko mouse was analyzed as a control, as indicated in the "genotype group" sample characteristic.