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

下丘脑驱动的抗衰老过程影响阿尔茨海默氏病小鼠模型

• 批准号: 10582631
• 负责人: TAMAS L HORVATH
• 金额: $ 64.61万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582631
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Animal Experiments; Animal Model; Animals; Behavioral; Biochemical; Biochemistry; Biological Markers; Brain; Brain Pathology; Caloric Restriction; Calories; Cell physiology; Clinical; Clinical Trials; Control Animal; Dementia; Development; Disease; Electrophysiology (science); Etiology; Evaluation; FGF21 gene; Genes; Geroscience; Histologic; Human; Human Amyloid Precursor Protein; Hunger; Hypothalamic structure; Impaired cognition; Impairment; Intervention; Life Expectancy; Link; Mediating; Metabolism; Methods; Modeling; Neuronal Dysfunction; Neurons; Nutrient; Outcome Study; Pathologic; Pathology; Peptides; Prevalence; Primates; Process; Publishing; Rat Transgene; Rattus; Symptoms; Testing; Tg2576; Therapeutic Intervention; Transgenic Mice; anti aging; effective therapy; fibroblast growth factor 21; in vivo; intervention effect; mouse model; mutant; novel strategies; novel therapeutics; pharmacologic; pre-clinical; presenilin-1

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.

本申请响应 RFA-AG-20-013，标题为 全世界 与衰老相关的 治疗阿尔茨海默病的方法 预期寿命的增加导致患病率急剧上升，从而影响 疾病，包括阿尔茨海默氏病（AD），没有有效的治疗方法可以阻止或减缓。 “老年科学疾病”。 广告， 和 新疗法的开发取得的进展令人失望，因为许多新化合物， 尽管在临床前水平上有初步的希望，但在临床试验中却失败了（Cummings et al., 2018）。 因此，检测衰老与 AD 之间机制联系的新方法。 细胞水平，导致与后来的认知障碍相关的前驱神经元功能障碍 痴呆是 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 促进 相关的 这 药理学的 表现 是 具体的 具体的 最近发表的初步结果表明，神经系统的不同步活动 我们还发现了 AD 大鼠和小鼠模型中的下丘脑饥饿症状。 表达刺豚鼠相关肽（AgRP）的神经元作为全身代谢的关键决定因素 这些观察共同推动了热量限制、衰老和更高的大脑功能。 该提案的中心假设是通过营养（热量限制）或 (FGF21) 干预措施将延迟电生理、行为和病理的发生 我们还捕获了下丘脑 AgRP 神经元的损伤。 为了检验这些假设，我们提出以下建议。 目标： 目标1 t 将检验热量限制和 FGF21 治疗抑制亚临床和 表达 AD 的转基因大鼠模型 (TgF344-AD) 的临床症状发展和脑病理学 突变型人类淀粉样前体蛋白 (APPswe) 和早老素 1 (PS1ΔE9) 基因。 具体目标 2 将 的 病理学 质疑下丘脑 AgRP 神经元对于介导作用至关重要的假设 热量限制和 FGF21 在调节亚临床和临床症状发展以及大脑中的作用 AD 转基因小鼠模型（5xFAD 和 Tg2576）。 为了实现这些具体目标，我们将利用 AD 的大鼠和小鼠模型以及营养和药理学 干预措施，结合体内电生理学、行为分析、生物化学和病理学 对照动物和实验动物的评价。 我们的研究将直接有力地分析衰老相关的系统和细胞之间的关系 使用电生理学（EEG）、行为学、组织学和生化方法来跟踪过程 这些研究的结果将立即表明已知动物模型中 AD 症状的发展。 可能的干预措施可以改变灵长类动物（包括人类）的AD发展。