Cheng Shaowu, Wani Willayat Y, Hottman David A, Jeong Angela, Cao Dongfeng, LeBlanc Kyle J, Saftig Paul, Zhang Jianhua, Li Ling
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Key Laboratory of Hunan Province for Integrated Traditional Chinese and Western Medicine on Prevention and Treatment of Cardio-Cerebral Disease, Hunan University of Chinese Medicine, Changsha, Hunan, China.
J Neurochem. 2017 Jul;142(2):297-304. doi: 10.1111/jnc.14048. Epub 2017 May 26.
Autophagy and lysosomal function are important for protein homeostasis and their dysfunction have been associated with Alzheimer's disease (AD). Increased immunoreactivities of an important lysosomal protease, cathepsin D (Cat D), are evident in amyloid plaques and neurons in patients with AD. This study tests the hypothesis that deleting one allele of the cathepsin D gene (Ctsd) impacts cerebral β-amyloidosis in amyloid-β precursor protein (APP)sw/PS1dE9 (APP/PS1) double transgenic mice. Despite a significant 38% decrease in Cat D level in APP/PS1/Ctsd+/- compared with APP/PS1/Ctsd+/+ mice, no changes in steady state levels and deposition of Aβ were found in the brain. There were also no differences in APP processing, the levels of two other Aβ-degrading proteases, the levels of autophagy related protein, such as LAMP2, P62, LC3-I, LC3-II, and Beclin-1, or the markers of neuroinflammation, observed between the APP/PS1/Ctsd+/+ and APP/PS1/Ctsd+/- mice. Our findings demonstrate that in wild-type mice, Cat D protein levels are either in excess or redundant with other factors in the brain, and at least one allele of Ctsd is dispensable for cerebral β-amyloidosis and autophagy in APP/PS1 transgenic mice.
自噬和溶酶体功能对蛋白质稳态至关重要，其功能障碍与阿尔茨海默病（AD）有关。在AD患者的淀粉样斑块和神经元中，一种重要的溶酶体蛋白酶组织蛋白酶D（Cat D）的免疫反应性增加明显。本研究检验了以下假设：在淀粉样前体蛋白（APP）sw/PS1dE9（APP/PS1）双转基因小鼠中，删除组织蛋白酶D基因（Ctsd）的一个等位基因会影响脑β-淀粉样变性。尽管与APP/PS1/Ctsd+/+小鼠相比，APP/PS1/Ctsd+/-小鼠的Cat D水平显著降低了38%，但在大脑中未发现Aβ的稳态水平和沉积有变化。在APP/PS1/Ctsd+/+和APP/PS1/Ctsd+/-小鼠之间，还未观察到APP加工、另外两种Aβ降解蛋白酶的水平、自噬相关蛋白（如LAMP2、P62、LC3-I、LC3-II和Beclin-1）的水平或神经炎症标志物存在差异。我们的研究结果表明，在野生型小鼠中，Cat D蛋白水平要么过量，要么与大脑中的其他因素冗余，并且在APP/PS1转基因小鼠中，Ctsd的至少一个等位基因对于脑β-淀粉样变性和自噬是可有可无的。
