Activity effects on Alzheimer neuropathology & dementia

描述（由申请人提供）：流行病学证据表明，持续的精神或体力活动可能会减弱阿尔茨海默病的认知能力下降，或延迟其发作。 然而，有一些相互矛盾的研究没有显示出增加阿尔茨海默氏症患者的认知活动或运动的益处。此外，另一种假设表明，一些患者在成年早期容易患上阿尔茨海默病，并且没有认知能力或倾向于从事精神刺激活动。 本提案中提出的实验旨在建立正在进行的精神或身体活动与携带淀粉样前体蛋白（APP）瑞典突变的转基因小鼠的认知状态之间的因果关系。这些转基因小鼠在大约10个月大时开始出现阿尔茨海默样淀粉样斑块。当喂食补充有同型半胱氨酸的叶酸缺乏饮食3个月时，APP转基因小鼠而不是野生型对照小鼠发生了胰腺特异性细胞死亡。因此，我们不仅能够确定增加身体或精神活动是否会改善认知能力，而且还能够确定它是否会影响细胞死亡或淀粉样蛋白斑块形成的速度，这些信息在人类阿尔茨海默病患者中无法获得。 总之，拟议实验提供的数据将告知我们认知刺激活动或体育锻炼作为治疗或预防措施在对抗阿尔茨海默病方面的潜在有效性。

DESCRIPTION (provided by applicant): Epidemiological evidence suggests that ongoing mental or physical activity may attenuate the cognitive decline of Alzheimer's disease, or delay its onset. However, there are conflicting studies that do not show a benefit for increased cognitive activity or exercise for Alzheimer's patients. In addition, an alternate hypothesis suggests that some patients are predisposed to get Alzheimer's disease by early adulthood, and do not have the cognitive capacity or inclination to engage in mentally stimulating activity. The experiments proposed in this proposal are designed to establish cause-and-effect relationships between ongoing mental or physical activity and cognitive status in transgenic mice bearing the Swedish mutation of the amyloid precursor protein (APP). These transgenic mice develop Alzheimer-like amyloid plaques starting at approximately 10 months of age. When fed a folate-deficient diet supplemented with homocysteine for 3 months, APP transgenic mice, but not wild-type control mice, develop hippocampal-specific cell death. Thus we will be able to determine not only whether increased physical or mental activity improves cognitive performance but also whether it affects the rate of cell death or amyloid plaque formation, information that is not obtainable in human Alzheimer patients. Together, the data provided by the proposed experiments will inform us as to the potential effectiveness of cognitively stimulating activities or physical exercise as therapeutic or preventative measures in the fight against Alzheimer's disease.