Cathepsin B Improves -Amyloidosis and Learning and Memory in Models of Alzheimer's Disease
Cathepsin B Improves -Amyloidosis and Learning and Memory in Models of Alzheimer's Disease
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DOI：
10.1007/s11481-016-9721-6
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发表时间：
2017-06-01
影响因子：
6.2
通讯作者：
Kiyota, Tomomi
中科院分区：
文献类型：
--
作者：
Embury, Christine M.;Dyavarshetty, Bhagyalaxmi;Kiyota, Tomomi
淀粉样蛋白(A)前体蛋白（APP）代谢通过神经元内溶酶体途径参与A的加工和分泌。在阿尔茨海默病（AD）中，APP的失调导致A过量和神经元功能障碍；这表明神经元APP/A转运可以作为治疗目标。组织蛋白酶B （CatB）是一种能降低a水平的溶酶体半胱氨酸蛋白酶。然而，catb -调制A是否能改善AD患者的学习和记忆功能缺陷尚不清楚。为此，用表达CatB的重组腺病毒感染祖神经元，并回收细胞裂解液进行蛋白质组学分析。结果证明了Lamp1的解除以及CatB与神经元吞噬体网络之间的联系。海马注射表达CatB的腺相关病毒降低了A水平，增加了Lamp1，改善了学习和记忆。这些发现与c-fos +细胞的出现有关。结果支持CatB可以通过溶酶体途径加速A代谢，从而减少ad相关的记忆缺陷的观点。
Amyloid- (A) precursor protein (APP) metabolism engages neuronal endolysosomal pathways for A processing and secretion. In Alzheimer's disease (AD), dysregulation of APP leads to excess A and neuronal dysfunction; suggesting that neuronal APP/A trafficking can be targeted for therapeutic gain. Cathepsin B (CatB) is a lysosomal cysteine protease that can lower A levels. However, whether CatB-modulation of A improves learning and memory function deficits in AD is not known. To this end, progenitor neurons were infected with recombinant adenovirus expressing CatB and recovered cell lysates subjected to proteomic analyses. The results demonstrated Lamp1 deregulation and linkages between CatB and the neuronal phagosome network. Hippocampal injections of adeno-associated virus expressing CatB reduced A levels, increased Lamp1 and improved learning and memory. The findings were associated with the emergence of c-fos + cells. The results support the idea that CatB can speed A metabolism through lysosomal pathways and as such reduce AD-associated memory deficits.