Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice.
Loss of kallikrein-related peptidase 7 exacerbates amyloid pathology in Alzheimer's disease model mice.
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DOI：
10.15252/emmm.201708184
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发表时间：
2018-03
影响因子：
11.1
通讯作者：
Tomita T
中科院分区：
文献类型：
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作者：
Kidana K;Tatebe T;Ito K;Hara N;Kakita A;Saito T;Takatori S;Ouchi Y;Ikeuchi T;Makino M;Saido TC;Akishita M;Iwatsubo T;Hori Y;Tomita T
淀粉样蛋白β (Aβ)作为老年斑沉积是阿尔茨海默病（AD）患者大脑的病理标志之一。此外，在阿尔茨海默病的大脑中发现了神经胶质细胞的激活，尽管星形胶质细胞的确切病理作用尚不清楚。在这里，我们发现了一种星形胶质细胞衍生的Aβ降解酶，即激肽素相关肽酶7 （KLK7）。AD患者大脑中KLK7 mRNA的表达明显降低。Klk7的消融加重了AD模型小鼠硫黄素S阳性Aβ的病理变化。在原代星形胶质细胞中，Aβ处理可上调Klk7的表达，表明Klk7受Aβ诱导反应的稳态调节。最后，我们发现美国食品和药物管理局批准的抗痴呆药物美金刚可以特异性地增加星形胶质细胞中Klk7和Aβ降解活性的表达。这些数据表明，KLK7是参与AD发病的星形胶质细胞降解和清除沉积的Aβ的重要酶。
Deposition of amyloid‐β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein‐related peptidase 7 (KLK7) as an astrocyte‐derived Aβ degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S‐positive Aβ pathology in AD model mice. The expression of Klk7 was upregulated by Aβ treatment in the primary astrocyte, suggesting that Klk7 is homeostatically modulated by Aβ‐induced responses. Finally, we found that the Food and Drug Administration‐approved anti‐dementia drug memantine can increase the expression of Klk7 and Aβ degradation activity specifically in the astrocytes. These data suggest that KLK7 is an important enzyme in the degradation and clearance of deposited Aβ species by astrocytes involved in the pathogenesis of AD.