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缓阿尔茨海默病的认知能力下降，或推迟其发病。然而，有一些相互矛盾的研究表明，增加认知活动或锻炼对阿尔茨海默氏症患者没有好处。此外，另一种假设表明，一些患者在成年早期就容易患上阿尔茨海默氏症，并且没有认知能力或从事精神刺激活动的倾向。这项提议中提出的实验旨在建立正在进行的精神或体力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个月大的时候开始形成类似阿尔茨海默氏症的淀粉样斑块。当缺乏叶酸和同型半胱氨酸的饮食喂养3个月时，APP转基因小鼠，而不是野生型对照小鼠，发生海马区特异性细胞死亡。因此，我们将不仅能够确定增加的体力或精神活动是否改善认知能力，而且还能够确定它是否影响细胞死亡或淀粉样斑块形成的比率，这些信息在人类阿尔茨海默病患者中是无法获得的。总之，拟议的实验提供的数据将告诉我们，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.