RIPK1 mediates a disease-associated microglial response in Alzheimer's disease
RIPK1 mediates a disease-associated microglial response in Alzheimer's disease
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DOI：
10.1073/pnas.1714175114
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发表时间：
2017-10-10
影响因子：
11.1
通讯作者：
Yuan, Junying
中科院分区：
文献类型：
--
作者：
Ofengeim, Dimitry;Mazzitelli, Sonia;Yuan, Junying
小胶质细胞功能障碍在阿尔茨海默病(AD)中起重要作用。在这里，我们研究了RIPK1在小胶质细胞介导AD发病机制中的作用。RIPK1在人AD脑内高表达于小胶质细胞。利用淀粉样前体蛋白(APP)/早老素1(PS1)转基因小鼠模型，我们发现通过药物和遗传手段抑制RIPK1可以减少淀粉样蛋白负荷、炎性细胞因子水平和记忆障碍。此外，抑制RIPK1在体外可促进Aβ的小胶质细胞降解。我们对APP/PS1小鼠成体小胶质细胞的转录谱进行了表征，并确定了RIPK1在调节小胶质细胞CH25H和Cst7表达中的作用。Cst7是疾病相关小胶质细胞(DAM)的标志，编码内体/溶酶体组织蛋白抑制剂Cystatin F。我们提供了证据，RIPK1介导的Cst7诱导导致溶酶体途径的损害。这些数据表明，RIPK1可能在向大坝状态的转变过程中介导了一个关键的检查点。总之，我们的研究强调了一种非细胞死亡机制，通过这种机制，RIPK1的激活介导了DAM表型的诱导，包括炎症反应和吞噬活性降低，并将RIPK1介导的小胶质细胞转录与AD的病因联系起来。我们的结果支持RIPK1是治疗AD的一个重要的治疗靶点。
Dysfunction of microglia is known to play an important role in Alzheimer's disease (AD). Here, we investigated the role of RIPK1 in microglia mediating the pathogenesis of AD. RIPK1 is highly expressed by microglial cells in human AD brains. Using the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model, we found that inhibition of RIPK1, using both pharmacological and genetic means, reduced amyloid burden, the levels of inflammatory cytokines, and memory deficits. Furthermore, inhibition of RIPK1 promoted microglial degradation of A beta in vitro. We characterized the transcriptional profiles of adultmicroglia from APP/PS1mice and identified a role for RIPK1 in regulating the microglial expression of CH25H and Cst7, a marker for disease-associated microglia (DAM), which encodes an endosomal/lysosomal cathepsin inhibitor named Cystatin F. We present evidence that RIPK1-mediated induction of Cst7 leads to an impairment in the lysosomal pathway. These data suggest that RIPK1 may mediate a critical checkpoint in the transition to the DAM state. Together, our study highlights a non-cell death mechanism by which the activation of RIPK1 mediates the induction of a DAM phenotype, including an inflammatory response and a reduction in phagocytic activity, and connects RIPK1-mediated transcription in microglia to the etiology of AD. Our results support that RIPK1 is an important therapeutic target for the treatment of AD.