Rao Shailaja Kishan, Ross Jordan M, Harrison Fiona E, Bernardo Alexandra, Reiserer Randall S, Reiserer Ronald S, Mobley James A, McDonald Michael P
Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Medicine, Vanderbilt University, Nashville, TN 37204, USA; Program in Neuroscience, Vanderbilt University, Nashville, TN 37204, USA.
Neurobiol Dis. 2015 Jun;78:45-55. doi: 10.1016/j.nbd.2015.03.018. Epub 2015 Mar 25.
Physical exercise may provide protection against the cognitive decline and neuropathology associated with Alzheimer's disease, although the mechanisms are not clear. In the present study, APP/PSEN1 double-transgenic and wild-type mice were allowed unlimited voluntary exercise for 7months. Consistent with previous reports, wheel-running improved cognition in the double-transgenic mice. Interestingly, the average daily distance run was strongly correlated with spatial memory in the water maze in wild-type mice (r(2)=.959), but uncorrelated in transgenics (r(2)=.013). Proteomics analysis showed that sedentary transgenic mice differed significantly from sedentary wild-types with respect to proteins involved in synaptic transmission, cytoskeletal regulation, and neurogenesis. When given an opportunity to exercise, the transgenics' deficiencies in cytoskeletal regulation and neurogenesis largely normalized, but abnormal synaptic proteins did not change. In contrast, exercise enhanced proteins associated with cytoskeletal regulation, oxidative phosphorylation, and synaptic transmission in wild-type mice. Soluble and insoluble Aβ40 and Aβ42 levels were significantly decreased in both cortex and hippocampus of active transgenics, suggesting that this may have played a role in the cognitive improvement in APP/PSEN1 mice. β-secretase was significantly reduced in active APP/PSEN1 mice compared to sedentary controls, suggesting a mechanism for reduced Aβ. Taken together, these data illustrate that exercise improves memory in wild-type and APP-overexpressing mice in fundamentally different ways.
体育锻炼可能对与阿尔茨海默病相关的认知衰退和神经病理学具有保护作用，尽管其机制尚不清楚。在本研究中，对APP/PSEN1双转基因小鼠和野生型小鼠进行了7个月的无限制自愿运动。与先前的报道一致，转轮运动改善了双转基因小鼠的认知能力。有趣的是，野生型小鼠的平均每日跑步距离与水迷宫中的空间记忆密切相关（r(2)=.959），而在转基因小鼠中则无相关性（r(2)=.013）。蛋白质组学分析表明，久坐不动的转基因小鼠与久坐不动的野生型小鼠在参与突触传递、细胞骨架调节和神经发生的蛋白质方面存在显著差异。当有机会运动时，转基因小鼠在细胞骨架调节和神经发生方面的缺陷基本恢复正常，但异常的突触蛋白没有变化。相比之下，运动增强了野生型小鼠中与细胞骨架调节、氧化磷酸化和突触传递相关的蛋白质。活跃的转基因小鼠的皮质和海马体中可溶性和不溶性Aβ40和Aβ42水平均显著降低，这表明这可能在APP/PSEN1小鼠的认知改善中发挥了作用。与久坐不动的对照组相比，活跃的APP/PSEN1小鼠中的β-分泌酶显著降低，这表明了Aβ减少的一种机制。综上所述，这些数据表明运动以根本不同的方式改善了野生型小鼠和APP过表达小鼠的记忆。
