Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Department of Neuroscience, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Neuron. 2021 Apr 21;109(8):1283-1301.e6. doi: 10.1016/j.neuron.2021.02.010. Epub 2021 Mar 5.
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.
TREM2 功能丧失突变强烈增加阿尔茨海默病 (AD) 的风险。Trem2 缺失已揭示了在β-淀粉样蛋白前临床模型中的保护 Trem2 功能，β-淀粉样蛋白是 AD 诊断前阶段的一个突出特征。TREM2 如何影响以 tau 介导的神经退行性病变为特征的 AD 后期阶段尚不清楚。为了了解 Trem2 在β-淀粉样蛋白和 tau 病理学背景下的功能，我们研究了单独表达突变 tau 的 pR5-183 小鼠模型和 TauPS2APP 小鼠中 Trem2 缺失的情况，其中β-淀粉样蛋白病理学加剧了 tau 病理学和神经退行性病变。这些模型中的单细胞 RNA 测序显示，TauPS2APP 小鼠中存在强烈的与疾病相关的小胶质细胞 (DAM) 激活，这种激活依赖于淀粉样蛋白和 Trem2。在存在β-淀粉样蛋白病理学的情况下，Trem2 缺失进一步加剧了 tau 积累和扩散，并促进了脑萎缩。在没有β-淀粉样蛋白病理学的情况下，Trem2 缺失不会影响这些过程。因此，TREM2 通过限制β-淀粉样蛋白促进致病性 tau 扩散的程度，可能会减缓 AD 进展并减少 tau 驱动的神经退行性病变。
