Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model
Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model
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可溶性 TREM2 通过调节阿尔茨海默病模型中的小胶质细胞功能来改善病理表型。
DOI：
10.1038/s41467-019-09118-9
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发表时间：
2019-03-25
影响因子：
16.6
通讯作者：
Chen, Xiao-Fen
中科院分区：
文献类型：
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作者：
Zhong, Li;Xu, Ying;Chen, Xiao-Fen
髓样细胞上表达的触发受体2（TREM2）是一种与阿尔茨海默病（AD）风险遗传相关的小胶质细胞表面受体。蛋白水解产物可溶性TREM2（sTREM2）在脑脊液中丰富，并且其水平与神经元损伤标志物正相关。为了深入了解sTREM2的病理作用，我们通过直接立体定位注射重组sTREM2蛋白或通过腺相关病毒（AAV）介导的表达研究了5xFAD小鼠（AD模型）脑中的sTREM2。我们发现sTREM2减少淀粉样斑块负荷并挽救空间记忆和长时程增强的功能缺陷。重要的是，sTREM2增强小胶质细胞增殖、迁移、在淀粉样斑块附近聚集以及A β的摄取和降解。小胶质细胞的消耗消除了sTREM2的神经保护作用。我们的研究证明了sTREM2对淀粉样病变和相关毒性的保护作用，并表明增加sTREM2可用于AD治疗。
Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer's disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of A beta. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.