INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
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DOI：
10.1016/j.isci.2023.106375
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发表时间：
2023-03-28
期刊：
影响因子：
5.8
通讯作者：
Tomita, Taisuke
中科院分区：
文献类型：
--
作者：
Iguchi, Akihiro;Takatori, Sho;Tomita, Taisuke
TREM2功能丧失变异与阿尔茨海默病（AD）的遗传关联表明小胶质细胞在AD发病机制中的保护作用。TREM2的功能缺陷会破坏淀粉样蛋白斑块周围的小胶质细胞聚集，损害它们对AD的转录反应，并加重神经营养不良。然而，这些表型背后的分子机制仍不清楚。在这项研究中，我们研究了另一个AD风险基因INPP5D的病理作用，INPP5D编码小胶质细胞中表达的磷酸肌苷PI(3,4,5)P-3磷酸酶。在tyrobp缺失的TREM2功能丧失小鼠模型中，Inpp5d单倍体缺失恢复了小胶质细胞与a β斑块的关联，部分恢复了斑块压实和星形胶质细胞形成，并减少了磷酸化的tau（+）营养不良的神经细胞。机制分析表明，TREM2/TYROBP和INPP5D对PI(3,4,5)P-3信号通路以及参与肌动蛋白组装的磷酸化蛋白发挥相反的作用。我们的研究结果表明，INPP5D作用于TREM2/TYROBP下游，调节小胶质屏障对抗A β毒性，从而调节A β依赖性tau的病理转化。
The genetic associations of TREM2 loss-of-function variants with Alzheimer dis-ease (AD) indicate the protective roles of microglia in AD pathogenesis. Functional deficiencies of TREM2 disrupt microglial clustering around amyloid beta (A beta) plaques, impair their transcriptional response to AD, and worsen neuritic dystrophy. How-ever, the molecular mechanism underlying these phenotypes remains unclear. In this study, we investigated the pathological role of another AD risk gene, INPP5D, encoding a phosphoinositide PI(3,4,5)P-3 phosphatase expressed in microglia. In a Tyrobp-deficient TREM2 loss-of-function mouse model, Inpp5d haplodeficiency restored the association of microglia with A beta plaques, partially restored plaque compaction, and astrogliosis, and reduced phosphorylated tau(+) dystrophic neu-rites. Mechanistic analyses suggest that TREM2/TYROBP and INPP5D exert opposing effects on PI(3,4,5)P-3 signaling pathways as well as on phosphoproteins involved in the actin assembly. Our results suggest that INPP5D acts downstream of TREM2/TYROBP to regulate the microglial barrier against A beta toxicity, thereby modulates A beta-dependent pathological conversion of tau.