Effect of Aging on Efficacy of Alzheimer-focused Therapeutic Strategies

阿尔茨海默病(AD)是最常见的神经退行性疾病，在中国有超过500万人受到影响 美国没有有效的治疗方法来预防、阻止或逆转这种疾病。尽管衰老是 阿尔茨海默病最重要的非遗传危险因素，幼鼠已用于绝大多数临床前 研究AD相关的小鼠模型，主要是出于实用和经济方面的原因。即使在很小的时候，这些 模型与AD有几个共同的病理特征。然而，它们显然不能完全模拟复杂性 人类的状况。我们假设衰老的小鼠模型将模拟人类的情况 在老年小鼠模型中评估候选疗法将比年轻小鼠模型更大的程度 在以后的临床试验中更好地预测这些疗法的疗效。在此UH2/UH3提案中，我们将澄清 自然衰老对人淀粉样前体蛋白转基因小鼠表型的影响 J20--使用最广泛的AD相关小鼠模型之一。此外，我们还将比较两种药物的疗效 这一品系在小鼠和老年鼠身上都有很有前途的候选疗法。而针对淀粉样蛋白-β(Aβ)的策略 在过去的十年里，它们理所当然地受到了相当大的关注，但仍不清楚它们是否会变成 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了这种治疗 与抗癫痫药物左乙拉西坦和遗传减少的tau改善突触，网络和 Happ-J20小鼠的认知功能障碍，这些发现已经被其他研究小组证实 独立的鼠标模型。然而，这些策略是否也有影响还有待确定 对长期暴露于病理性升高的Aβ水平的老化大脑的有益影响。我们 因此建议研究左乙拉西坦治疗老年患者的疗效和tau基因的减少。 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.