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

基本信息

  • 批准号:
    10374026
  • 负责人:
  • 金额:
    $ 64.61万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
本申请响应标题为RFA-AG-20-013的要求 全球 衰老相关 老年痴呆症的治疗方法 预期寿命的增加导致了流行率的急剧上升,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停止或减缓 “老年病”。 AD, 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(Cummings等,2018年)。最大的风险 AD的因素是老化。因此,新的方法检测衰老和AD之间的机械联系, 细胞水平,导致前驱神经元功能障碍与后来的认知障碍, 痴呆是AD的核心特征,对于确定有可能改变AD的治疗干预至关重要。 病程。 我们 先于 促进 相关 的 药理 表现 是 具体 具体 最近发表的初步结果表明,神经元集合的不同步活动 在AD的大鼠和小鼠模型中的症状发作。我们还发现了下丘脑饥饿- 神经元表达Agouti相关肽(AgRP)作为全身代谢的关键决定因素 限制卡路里摄入,衰老和大脑功能的提高这些观察共同推动了 这一建议的中心假设,即通过营养(热量限制)或 (FGF 21)干预将延迟电生理,行为和病理的一次发作 AD动物模型中的损伤。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。为了验证这些假设,我们提出以下建议: 目的: 要求1 不 将检验热量限制和FGF 21治疗抑制亚临床和 表达AD的转基因大鼠模型(TgF 344-AD)中的临床症状发展和脑病理学 突变型人淀粉样前体蛋白(APPswe)和早老素1(PS1ΔE9)基因。 具体目标2将 的 病理 询问下丘脑AgRP神经元对介导效应至关重要的假设 热量限制和FGF 21在亚临床和临床症状发展和脑中的调节 在AD的转基因小鼠模型(5xFAD和Tg 2576)中。 为了实现这些特定目标,我们将利用AD大鼠和小鼠模型, 干预,体内电生理学,行为分析,生物化学和病理学的组合, 评价对照和实验动物。 我们的研究将直接和有力地分析与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、组织学和生物化学方法来跟踪 在已知的动物模型中AD的症状发展。这些研究的结果将立即表明, 改变包括人类在内的灵长类动物AD发展的可能干预措施。

项目成果

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TAMAS L HORVATH其他文献

TAMAS L HORVATH的其他文献

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{{ truncateString('TAMAS L HORVATH', 18)}}的其他基金

The role of mitochondrial dynamics in diet-influenced regulation of food intake and adiposity
线粒体动力学在饮食影响的食物摄入和肥胖调节中的作用
  • 批准号:
    10154482
  • 财政年份:
    2021
  • 资助金额:
    $ 64.61万
  • 项目类别:
The role of mitochondrial dynamics in diet-influenced regulation of food intake and adiposity
线粒体动力学在饮食影响的食物摄入和肥胖调节中的作用
  • 批准号:
    10352446
  • 财政年份:
    2021
  • 资助金额:
    $ 64.61万
  • 项目类别:
The role of mitochondrial dynamics in diet-influenced regulation of food intake and adiposity
线粒体动力学在饮食影响的食物摄入和肥胖调节中的作用
  • 批准号:
    10520062
  • 财政年份:
    2021
  • 资助金额:
    $ 64.61万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 64.61万
  • 项目类别:
AgRP neurons promote the effects of calorie restriction on lifespan
AgRP 神经元促进热量限制对寿命的影响
  • 批准号:
    9263491
  • 财政年份:
    2017
  • 资助金额:
    $ 64.61万
  • 项目类别:
In vivo and in vitro systems to validate geronic proteins and their mechanisms of action
用于验证老年蛋白及其作用机制的体内和体外系统
  • 批准号:
    9422316
  • 财政年份:
    2017
  • 资助金额:
    $ 64.61万
  • 项目类别:
Feeding Driven by POMC Neurons
POMC 神经元驱动的进食
  • 批准号:
    9325239
  • 财政年份:
    2017
  • 资助金额:
    $ 64.61万
  • 项目类别:
In vivo and in vitro systems to validate geronic proteins and their mechanisms of action
用于验证老年蛋白及其作用机制的体内和体外系统
  • 批准号:
    9264636
  • 财政年份:
    2016
  • 资助金额:
    $ 64.61万
  • 项目类别:
AgRP neurons regulate bone remodeling in aging
AgRP 神经元调节衰老过程中的骨重塑
  • 批准号:
    8321998
  • 财政年份:
    2011
  • 资助金额:
    $ 64.61万
  • 项目类别:
AgRP neurons regulate bone remodeling in aging
AgRP 神经元调节衰老过程中的骨重塑
  • 批准号:
    8688867
  • 财政年份:
    2011
  • 资助金额:
    $ 64.61万
  • 项目类别:
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