Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease
Voluntary exercise decreases amyloid load in a transgenic model of Alzheimer's disease
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DOI：
10.1523/jneurosci.0496-05.2005
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发表时间：
2005-04-27
影响因子：
5.3
通讯作者：
Cotman, CW
中科院分区：
文献类型：
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作者：
Adlard, PA;Perreau, VM;Cotman, CW
阿尔茨海默病（AD）是一种进行性神经退行性疾病，目前针对其潜在疾病机制的治疗方法很少。然而，近期的流行病学研究表明，生活方式的改变可能会减缓AD的发病/进展。在此，我们使用TgCRND8小鼠直接研究运动与AD级联反应之间的相互作用。5个月的自主运动导致额叶皮质（减少38%；p = 0.018）、海马体水平的皮质（减少53%；p = 0.0003）以及海马体（减少40%；p = 0.06）中的细胞外β - 淀粉样蛋白（Aβ）斑块减少。这与皮质中Aβ1 - 40（减少35%；p = 0.005）和Aβ1 - 42（减少22%；p = 0.04）（酶联免疫吸附测定）的减少有关。其机制似乎是由短期运动后淀粉样前体蛋白（APP）的加工过程改变所介导的，因为1个月的运动减少了APP的蛋白水解片段[对于α - C末端片段（α - CTF），减少54%，p = 0.04；对于β - CTF，减少35%，p = 0.03]。这种效应与脑啡肽酶和胰岛素降解酶的mRNA/蛋白质变化无关，相反，可能涉及已知会影响APP加工且受运动调节的神经元代谢变化。长期运动还提高了TgCRND8动物在莫里斯水迷宫中的学习速度，在（6天中的）前3天试验中，逃避潜伏期显著（p < 0.02）缩短。支持现有的流行病学研究，这项研究表明，运动是一种简单的行为干预措施，足以抑制TgCRND8小鼠模型中类似AD的神经病理学的正常进展。
Alzheimer's disease ( AD) is a progressive neurodegenerative disorder for which there are few therapeutics that affect the underlying disease mechanism. Recent epidemiological studies, however, suggest that lifestyle changes may slow the onset/progression of AD. Here we have used TgCRND8 mice to examine directly the interaction between exercise and the AD cascade. Five months of voluntary exercise resulted in a decrease in extracellular amyloid-beta (A beta) plaques in the frontal cortex (38%; p = 0.018), the cortex at the level of the hippocampus (53%; p = 0.0003), and the hippocampus (40%; p = 0.06). This was associated with decreased cortical A beta 1 - 40 (35%; p = 0.005) and A beta 1 - 42 (22%; p = 0.04) (ELISA). The mechanism appears to be mediated by a change in the processing of the amyloid precursor protein (APP) after short-term exercise, because 1 month of activity decreased the proteolytic fragments of APP [ for alpha-C-terminal fragment (alpha-CTF), 54% and p = 0.04; for beta-CTF, 35% and p = 0.03]. This effect was independent of mRNA/protein changes in neprilysin and insulin-degrading enzyme and, instead, may involve neuronal metabolism changes that are known to affect APP processing and to be regulated by exercise. Long-term exercise also enhanced the rate of learning of TgCRND8 animals in the Morris water maze, with significant ( p < 0.02) reductions in escape latencies over the first 3 ( of 6) trial days. In support of existing epidemiological studies, this investigation demonstrates that exercise is a simple behavioral intervention sufficient to inhibit the normal progression of AD-like neuropathology in the TgCRND8 mouse model.