ENVIRONMENTAL ENRICHMENT EFFECTS IN ALZHEIMER'S DISEASE TRANSGENIC MICE

虽然回溯性研究表明，终生高精神活动模式可以预防阿尔茨海默病(AD)，但前瞻性的纵向研究尚未完成。同样，社会和/或身体活动对降低AD风险的贡献在对照临床研究中也没有得到充分的评估，也没有在AD患者中进行长期、密集的认知康复的潜在好处。AD转基因小鼠的出现使得在完全对照的纵向研究中研究这些问题成为可能。我们的初步研究表明，“完全”的环境丰富(例如，认知、社交和身体活动)对AD转基因小鼠的认知损害既有保护作用，也有治疗作用？这在不影响大脑β-淀粉样蛋白沉积的情况下。本项目将首先阐明每一个人的作用 对完全性脑损伤保护能力有贡献的成分(如认知、社交和身体) 环境浓缩；这种浓缩成分的分离在临床研究中是不可能实现的。其次，该项目将评估持续环境浓缩和会话限制环境浓缩作为治疗认知受损的AD转基因小鼠的潜力。所有AD患者的认知康复治疗都是会话受限的，因此在AD转基因模型中研究这一方案具有重要意义。第三，将评估各种大脑神经病理和神经化学过程，这些过程可能机械地涉及环境浓缩或其各种成分活动提供的认知益处。这些过程包括神经发生、神经变性、氧化应激、神经炎症和生长因子调节。总而言之，这个项目的研究 对公众健康具有重大意义，因为它们调查了“可改变的”因素(认知、社会、身体活动)预防或治疗阿尔茨海默病的可能性，并对其中可能涉及的可能的细胞/分子机制提供了重要的见解。

Although retrospective studies suggest that a lifelong pattern of high mental activity is protective against Alzheimer's Disease (AD), prospective longitudinal studies have not been done. As well, the contribution of social and/or physical activity to AD risk-reduction has not been adequately evaluated in controlled clinical studies nor has the potential benefit of long-term, intensive cognitive rehabilitation in AD patients. The availability of AD transgenic mice make it possible to investigate these issues in fully-controlled longitudinal studies. Our preliminary studies indicate that "complete" environmental enrichment (e.g., cognitive, social, and physical activity) is both protective and therapeutic against cognitive impairment in AD transgenic mice ? this, without affecting brain beta-amyloid deposition. The present project will first elucidate the role of each contributing component (e.g., cognitive,social, and physical) to the protective ability of complete environmental enrichment; this isolation of enrichment's contributing components is impossible to achieve in clinical studies. Second, this project will evaluate the potential of both continous and session-restricted environmental enrichment as a treatment to cognitively-impaired AD transgenic mice. All cognitive rehabilitative therapeutic in AD patients are session-restricted, so it is important to investigate this protocol in AD transgenic models. Third, a variety of brain neuropathologic and neurochemical processes will be assessed that could be mechanistically involved in the cognitive benefits provided by environmental enrichment or it's various component activities. These processes include neurogenesis, neurodegeneration, oxidative stress, neuroinflammation, and growth factor modulation. Collectively, the studies of this project are of substantial public health significance because they investigate the potential for "modifiable" factors (cognitive, social, physical activity) to protective against or treat AD, as well as provide important insight into likely cellular/molecular mechanisms that may be involved therein.