Role of Lifespan Intervention on the Regulation and Progression of Alzheimer's Disease

项目概要/摘要 我们的长期目标是确定能够预防阿尔茨海默病发病机制的治疗药物 （AD）。全球AD病例数量急剧上升，迫切需要开发新的 比目前批准的四种AD药物更有效的治疗方法， 症状缓解。迄今为止的每一项临床试验都未能证明AD的疾病改善疗效， 部分原因可能是我们对AD发病机制的了解有限， 与正常的健康衰老不同我们建议的总体目标是进一步了解 自噬-炎症网络失调的潜在机制， 随着年龄的增长而失调，并由病理条件加速。全身性炎症是这种疾病的生物标志物 失调，如其在包括心血管疾病在内的许多衰老相关疾病中的患病率所例示， 糖尿病、癌症和神经退行性疾病如阿尔茨海默病（AD）中的神经炎症。我们 假设驱动全身性炎症机制在衰老生物学中是共同的， AD，并提出针对全身炎症的共同特征的干预措施，通过调节 自噬-炎症网络可能具有作为预防转化的治疗剂的潜力， AD的发病机制，以及改善老年人群的健康寿命和寿命。为此 我们将结合使用遗传和药理学工具来了解哪些大脑特定细胞 类型可能通过mTOR依赖性和 调节炎症的mTOR独立机制。我们的研究结果将提供 在细胞水平上的见解和创新的治疗策略，以进一步研究。具体来说，我们将 研究有助于mTOR抑制的神经保护作用的单个细胞类型， 进行性AD，并确认和扩展有关散发性AD患者的寿命和健康寿命的有益影响的数据， 雷帕霉素预防性治疗AD。重要的是，由于年龄和遗传是主要的风险因素， AD，我们将评估临床前模型系统中的干预措施，该系统将衰老和遗传风险结合起来。 AD的因素。因此，我们将测试直接操纵AMPK对调节寿命的作用， 在正常衰老和AD易感模型中的健康寿命，以及MAG脂肪酶抑制在 正常健康衰老和AD发病机制中的作用，与雷帕霉素在小鼠模型中的作用相比 迟发性AD

Project Summary/Abstract Our long-term goal is to identify therapeutic agents that can prevent the pathogenesis of Alzheimer’s disease (AD). The number of AD cases is rising dramatically worldwide, and there is an urgent need to develop new therapies that are more efficacious than the four currently approved drugs for AD which provide only modest symptomatic relief. Every clinical trial to date has failed to demonstrate disease-modifying efficacy for AD, which may in part be due to our limited understanding of the mechanisms that precede the pathogenesis of AD, and that are distinct from normal healthy aging. The overall aims of our proposal are to further understand the mechanisms underlying dysregulation of the autophagy-inflammation network that becomes progressively dysregulated with age, and accelerated by pathological conditions. Systemic inflammation is a biomarker of this dysregulation, as exemplified by its prevalence in many aging-related disorders including cardiovascular disease, diabetes, cancers, and neuroinflammation in neurodegenerative disorders such Alzheimer’s disease (AD). We hypothesize that mechanisms which drive systemic inflammation are common to both the biology of aging and AD and propose that interventions which target the shared feature of systemic inflammation, via regulation of the autophagy-inflammation network, may have potential as therapeutic agents for the prevention of conversion to disease pathogenesis in AD, as well as improve healthspan and longevity in aging populations. For this proposal we will use a combination of genetic and pharmacological tools to understand which brain specific cell types may be involved in the regulation of the autophagy-inflammation network via both mTOR dependent and mTOR-independent mechanisms that modulate inflammation. Findings from our studies will provide mechanistic insights at a cellular level and innovative therapeutic strategies for further research. Specifically, we will investigate the individual cell types that contribute to the neuroprotective effects of mTOR inhibition in progressive AD, and confirm and extend the data on the beneficial effects of lifespan and healthspan in sporadic AD with prophylactic treatment of rapamycin. Critically, since age and genetics are the leading risk factors for AD, we will evaluate interventions in preclinical model systems that incorporate both aging and genetic risk factors for AD. We will therefore test the role of direct manipulation of AMPK on modulation of lifespan and healthspan in normal aging and in AD susceptible models, and the beneficial role of MAG lipase inhibition in normal healthy aging and in the pathogenesis of AD in comparison to the effects of rapamycin in a mouse model of late onset AD.