Chen Xuesong, Wagener John F, Ghribi Othman, Geiger Jonathan D
Department of Basic Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota Grand Forks, ND, USA.
Front Aging Neurosci. 2016 Jun 8;8:129. doi: 10.3389/fnagi.2016.00129. eCollection 2016.
Deficits in skeletal muscles contribute not only to the functional decline in people living with Alzheimer's disease (AD), but also to AD pathogenesis. We have shown that endolysosome dysfunction plays an important role in the development of AD pathological features in a cholesterol-fed rabbit model of AD. Interestingly we observed in skeletal muscle from the rabbit AD model increased deposition of Aβ, phosphorylated tau, and ubiquitin. Here, we tested the hypothesis that endolysosome dysfunction commonly occurs in skeletal muscle and brain in this rabbit model of AD. In skeletal muscle of rabbits fed a 2% cholesterol-enriched diet for 12 weeks we observed the presence of abnormally enlarged endolysosomes, in which were increased accumulations of free cholesterol and multiple AD marker proteins subject to misfolding and aggregation including Aβ, phosphorylated tau, and ubiquitin. Moreover, in skeletal muscle of rabbits fed the cholesterol-enriched diet we observed decreased specific activities of three different lysosome enzymes. Our results suggest that elevated levels of plasma cholesterol can disturb endolysosome structure and function as well as promote the development of AD-like pathological features in skeletal muscle and that these organellar changes might contribute to the development of skeletal muscle deficits in AD.
骨骼肌功能缺陷不仅会导致阿尔茨海默病（AD）患者的功能衰退，还会影响AD的发病机制。我们已经表明，在高胆固醇喂养的AD兔模型中，内溶酶体功能障碍在AD病理特征的发展中起重要作用。有趣的是，我们在兔AD模型的骨骼肌中观察到β淀粉样蛋白（Aβ）、磷酸化tau蛋白和泛素的沉积增加。在此，我们检验了一个假设，即在该兔AD模型中，内溶酶体功能障碍在骨骼肌和大脑中普遍存在。在喂食2%富含胆固醇饮食12周的兔子的骨骼肌中，我们观察到存在异常增大的内溶酶体，其中游离胆固醇以及包括Aβ、磷酸化tau蛋白和泛素在内的多种易发生错误折叠和聚集的AD标记蛋白的积累增加。此外，在喂食富含胆固醇饮食的兔子的骨骼肌中，我们观察到三种不同溶酶体酶的比活性降低。我们的结果表明，血浆胆固醇水平升高会扰乱内溶酶体的结构和功能，并促进骨骼肌中AD样病理特征的发展，并且这些细胞器变化可能导致AD患者骨骼肌功能缺陷的发展。
