Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice
Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice
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TREM2 沉默会加剧 P301S tau 转基因小鼠的 tau 病理、神经退行性变化和空间学习缺陷
DOI：
10.1016/j.neurobiolaging.2015.08.019
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发表时间：
2015-12-01
影响因子：
4.2
通讯作者：
Yu, Jin-Tai
中科院分区：
文献类型：
--
作者：
Jiang, Teng;Tan, Lan;Yu, Jin-Tai
Tau病理是包括阿尔茨海默病和额颞痴呆在内的几种神经退行性疾病的病理标志。作为这两种疾病的一个新的易感基因，TREM2基因编码一种由小胶质细胞唯一表达的免疫受体。最近，在阿尔茨海默病患者的大脑中发现了TREM2的表达和过度磷酸化的tau之间的相关性，这表明TREM2和tau的病理可能存在关联。然而，到目前为止，TREM2在tau病理中的作用尚不清楚。在这里，我们在P301S小鼠身上发现，在疾病进展过程中，TREM2在小胶质细胞中上调。大脑TREM2的沉默加重了P301S小鼠的tau病理。这种恶化可能归因于神经炎症诱导的tau激酶的过度激活。此外，在TREM2沉默后观察到更严重的神经退行性改变和空间学习障碍。我们的结果表明，TREM2通过限制神经炎症来减弱tau激酶的活性，从而保护tau病理。这些发现进一步表明，TREM2可能是tau相关神经退行性疾病的潜在治疗靶点。(C)2015 Elsevier Inc.保留所有权利。
Tau pathology is a pathological hallmark for several neurodegenerative diseases including Alzheimer's disease and frontotemporal dementia. As a novel susceptibility gene for these 2 diseases, triggering receptor expressed on myeloid cells 2 (TREM2) gene encodes an immune receptor that is uniquely expressed by microglia. Recently, a correlation between TREM2 expression and hyperphosphorylated tau has been revealed in the brain of Alzheimer's disease patients, suggesting a potential association between TREM2 and tau pathology. However, the role of TREM2 in tau pathology remains unclear thus far. Herein, using P301S mice, we showed that TREM2 was upregulated in microglia during disease progression. Silencing of brain TREM2 exacerbated tau pathology in P301S mice. This exacerbation might be attributed to neuroinflammation-induced hyperactivation of tau kinases. Additionally, more severe neurodegenerative changes and spatial learning deficits were observed following TREM2 silencing. Our results imply that TREM2 attenuates tau kinase activity through restriction of neuroinflammation, and thus protects against tau pathology. These findings further suggest that TREM2 may represent as a potential therapeutic target for tau-related neurodegenerative diseases. (C) 2015 Elsevier Inc. All rights reserved.