Effect of Aging on Efficacy of Alzheimer-focused Therapeutic Strategies

阿尔茨海默氏病（AD）是最常见的神经退行性疾病，在美国影响超过500万人。 没有有效的治疗方法可以预防，停止或逆转这种疾病。虽然衰老是 作为AD最重要的非遗传风险因素，年轻小鼠已用于绝大多数临床前研究。 在AD相关小鼠模型中的研究，主要是出于实践和经济原因。即使在年轻的时候，这些 模型与AD共享若干病理特征。然而，它们显然没有模拟完整的复杂性 人类的状况。我们假设，老年小鼠模型将模拟人类的条件， 在老年小鼠模型中评估候选疗法将 更好地预测这些疗法在以后的临床试验中的疗效。在UH 2/UH 3提案中，我们将阐明 人淀粉样前体蛋白（hAPP）转基因小鼠自然衰老表型影响 J20-最广泛使用的AD相关小鼠模型之一。此外，我们还将比较 有希望的候选疗法在年轻和老年小鼠从这个线。针对β淀粉样蛋白（Aβ）的策略 在过去的十年里，它们无疑受到了相当大的关注，但目前还不清楚它们是否会成为 在正在进行的临床试验中既有效又安全。我们在被广泛引用的出版物中报道， 随着抗癫痫药物左乙拉西坦和tau蛋白的遗传减少， hAPP-J20小鼠的认知功能障碍，这些发现已被其他研究组证实。 独立的小鼠模型。然而，还有待确定的是，这些战略是否也具有 长期暴露于病理性升高的Aβ水平的衰老大脑中的有益效果。我们 因此，建议研究左乙拉西坦治疗老年人的疗效和tau蛋白的遗传减少， hAPP-J20小鼠。

Alzheimer's disease (AD) is the most common neurodegenerative disorder, affecting over 5 million people in the U.S. No effective treatments are available to prevent, halt, or reverse the disease. Although aging is the most important nongenetic risk factor for AD, young mice have been used for the vast majority of preclinical studies in AD-related mouse models, mainly for practical and financial reasons. Even at young ages, these models share several pathological features with AD. However, they clearly do not simulate the full complexity of the human condition. We hypothesize that aged mouse models will simulate the human condition to a greater extent than young mouse models and that assessing candidate therapies in aged mouse models will better predict the efficacy of these therapies in later clinical trials. In this UH2/UH3 proposal, we will elucidate the phenotypic impact of natural aging in human amyloid precursor protein (hAPP) transgenic mice from line J20—one of the most extensively used AD-related mouse models. In addition, we will compare the efficacy of promising candidate therapies in young and old mice from this line. While strategies targeting amyloid-β (Aβ) have justifiably received considerable attention over the past decade, it is still unclear whether they will turn out to be both efficacious and safe in ongoing clinical trials. We reported in well-cited publications that treatment with the anti-epileptic drug levetiracetam and genetic reduction of tau ameliorate synaptic, network and cognitive dysfunction in hAPP-J20 mice, and these findings have been confirmed by other groups in independent mouse models. However, it remains to be determine whether these strategies also have beneficial effects in aging brains that have had longer exposures to pathologically elevated levels of Aβ. We therefore propose to investigate the efficacy of levetiracetam treatment and genetic reduction of tau in old hAPP-J20 mice.