Hypothalamus-driven anti-aging processes impact murine models of Alzheimer's Disease

本申请响应名为RFA-AG-20-013的 世界范围 与年龄相关的 阿尔茨海默氏症的治疗方法 预期寿命的增加导致患病率急剧上升，从而影响了 疾病，包括阿尔茨海默病(AD)。没有有效的治疗方法来阻止或减缓 “老年病”。 广告， 和 新疗法的开发进展令人失望，因为许多新化合物， 尽管最初在临床前水平有希望，但在临床试验中失败了(Cummings等人，2018年)。最大的风险 AD的致病因素是衰老。因此，新的方法检测衰老和AD之间的机制联系在 细胞水平，这导致前驱神经功能障碍与后来的认知障碍和 痴呆症是AD的核心特征，对于确定有可能改变的治疗干预措施至关重要 病程。 我们的 先于 推介 相关 这个 药理作用 表现形式 是 特定的 特定的 最近发表的和初步的结果表明，神经元集合的不同步活动 阿尔茨海默病大鼠和小鼠模型的症状出现。我们还确认了下丘脑的饥饿- 表达AgRp的神经元是系统代谢的关键决定因素 限制卡路里，衰老和更高的大脑功能。这些观察结果共同推动了 这一建议的中心假设是通过营养(卡路里限制)或 (FGF21)干预将延迟电生理、行为和病理的恢复 阿尔茨海默病动物模型的损害。我们还假设下丘脑AgRP神经元 对这些干预措施的有益效果至关重要。为了检验这些假设，我们提出了以下建议 目标： 目标1 T 将检验卡路里限制和FGF21治疗抑制亚临床和 表达AD的转基因大鼠(TgF344-AD)的临床症状和脑病理变化 突变的人淀粉样前体蛋白(APPSWE)和早老素1(PS1ΔE9)基因。 特定目标2将 的 病理学 质疑下丘脑AgRP神经元在中介作用中起关键作用的假设 热量限制和成纤维细胞生长因子21对亚临床和临床症状发育及脑的调节作用 在AD转基因小鼠模型(5xFAD和Tg2576)中。 为了实现这些特定的目标，我们将利用具有营养和药理作用的AD大鼠和小鼠模型 干预，体内电生理学、行为分析、生化和病理学的结合 对照动物和实验动物的评价。 我们的研究将直接而有力地分析衰老相关的系统和细胞之间的关系 使用电生理(EEG)、行为、组织学和生化方法跟踪过程 已知动物模型阿尔茨海默病的症状发展。这些研究的结果将立即表明 可能的干预措施来改变灵长类动物，包括人类的阿尔茨海默病的发展。

This application responds to RFA-AG-20-013 entitled Worldwide aging-associated Approaches to Alzheimer's increase in life expectancy has produced a dramatic rise in the prevalence, and thus impact of diseases, including Alzheimer's disease (AD). There is no effective treatment to halt or slow “Geroscience Disease”. AD, and progress made in the development of new therapies is disappointing since many new compounds, despite initial promise at the preclinical level, failed in clinical trials (Cummings et al., 2018). The biggest risk factor for AD is aging. Therefore, novel approaches detecting mechanistic link between aging and AD at the cellular level, that leads to prodromal neuronal dysfunctions associated with later cognitive impairment and dementia, core features of AD, are crucial for identifying therapeutic interventions that have potential to modify course of disease. Our precedes promoting relevant the pharmacological manifestation are Specific Specific recent published and preliminary results showed that dyssynchronous activity of neuronal ensembles onset of symptoms in rat and mouse models of AD. We also identified hypothalamic hunger- neurons expressing Agouti-related peptide (AgRP) as crucial determinant of systemic metabolism to calorie restriction, aging and higher brain functions. These observations collectively gave impetus to central hypothesis of this proposal, which is that suppression of aging by nutrient (calorie restriction) or (FGF21) interventions will delay t he onse of electrophysiological, behavioral and pathological of impairments in animal models of AD. We also hypothesize that hypothalamic AgRP neurons central to the beneficial effects of these interventions. To test these hypotheses, we propose the following Aims: Aim 1 t will test the hypothesis that calorie restriction and FGF21 treatment suppress subclinical and clinical symptom development and brain pathologies in a transgenic rat model (TgF344-AD) of AD expressing mutant human amyloid precursor protein (APPswe) and presenilin 1 (PS1ΔE9) genes. Specific Aim 2 will of pathologies interrogate the hypothesis that hypothalamic AgRP neurons are critical for mediating effects calorie restriction and FGF21 in modulation of subclinical and clinical symptoms development and brain in transgenic mouse models (5xFAD and Tg2576) of AD. To execute these Specific Aims we will utilize rat and mouse models of AD with nutrient and pharmacological interventions, the combination of in vivo electrophysiology, behavioral analyses, biochemistry and pathological evaluation of control and experimental animals. Our studies will directly and forcefully analyze the relationship between aging-related systemic and cellular processes using electrophysiological (EEG), behavioral, histological and biochemical methods to track symptoms development of AD in known animal models. The outcome of these studies will immediately suggest possible interventions to alter AD development in primates, including humans.