Kallikrein-8 inhibition attenuates Alzheimer's disease pathology in mice
Kallikrein-8 inhibition attenuates Alzheimer's disease pathology in mice
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DOI：
10.1016/j.jalz.2016.05.006
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发表时间：
2016-12-01
影响因子：
14
通讯作者：
Keyvani, Kathy
中科院分区：
文献类型：
--
作者：
Herring, Arne;Muenster, Yvonne;Keyvani, Kathy
简介：记忆丧失和焦虑增加是阿尔茨海默病（AD）的临床标志。激肽释放酶-8是一种与记忆获得和焦虑有关的蛋白酶，已知其mRNA在受AD影响的人类海马中上调。因此，激肽释放酶-8参与阿尔茨海默病的发病机制是可以想象的，但仍有待证明。方法：我们确定了在AD患者和转基因小鼠的过程中激肽释放酶-8 mRNA和蛋白质的大脑表达，并测试了激肽释放酶-8抑制对小鼠和原代胶质细胞中AD相关病理学的影响。激肽释放酶-8 mRNA和蛋白在AD的早期阶段在两个物种中上调。激肽释放酶-8抑制阻碍淀粉样蛋白前体蛋白加工，促进淀粉样蛋白（A β）清除血脑屏障，促进自噬，减少A β负荷和tau病理，增强神经可塑性，逆转焦虑的分子特征，并最终改善记忆和减少fear.Discussion：激肽释放酶-8是一个有前途的新的治疗AD的目标。(C)2016年6月，作者。爱思唯尔公司出版代表老年痴呆症协会这是CC BY-NC-ND许可下的开放获取文章。
Introduction: Memory loss and increased anxiety are clinical hallmarks of Alzheimer's disease (AD). Kallikrein-8 is a protease implicated in memory acquisition and anxiety, and its mRNA is known to be up-regulated in AD-affected human hippocampus. Therefore, an involvement of Kallikrein-8 in Alzheimer's pathogenesis is conceivable but remains to be proved.Methods: We determined the cerebral expression of Kallikrein-8 mRNA and protein during the course of AD in patients and in transgenic mice and tested the impact of Kallikrein-8 inhibition on AD-related pathology in mice and in primary glial cells.Results: Kallikrein-8 mRNA and protein were up-regulated in both species at incipient stages of AD. Kallikrein-8 inhibition impeded amyloidogenic amyloid-precursor-protein processing, facilitated amyloid (A beta) clearance across the blood-brain-barrier, boosted autophagy, reduced A beta load and tau pathology, enhanced neuroplasticity, reversed molecular signatures of anxiety, and ultimately improved memory and reduced fear.Discussion: Kallikrein-8 is a promising new therapeutic target against AD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association. This is an open access article under the CC BY-NC-ND license.