Hypothalamic and metabolic dysfunction in Alzheimer's disease

阿尔茨海默病的下丘脑和代谢功能障碍

• 批准号: 10323686
• 负责人: Makoto Ishii
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10323686
• 关键词: Adipocytes; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Atrophic; Attention; Award; Body Weight; Body Weight decreased; Brain; Brain region; Cells; Cerebrospinal Fluid; Clinical; Cognition; Cognitive; Cognitive deficits; Cre lox recombination system; Data; Dementia; Diagnostic; Disease; Disease Progression; Elderly; Event; Failure; Functional disorder; Genetic; Genomic approach; Goals; Homeostasis; Hormones; Human; Huntington Disease; Hypothalamic dysfunction; Hypothalamic structure; Impaired cognition; Individual; Intervention Trial; Knock-out; Knowledge; Leptin; Light; Longitudinal Studies; Medical Research; Memory impairment; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Molecular; Neuronal Dysfunction; Neurons; Outcome Study; Pathogenesis; Pathologic; Pathology; Pathway interactions; Peptides; Plasma; Population; Psyche structure; Public Health; Research; Research Institute; Role; Senile Plaques; Signal Pathway; Signal Transduction; Signaling Molecule; Synapses; Testing; Tg2576; Therapeutic; Transgenic Mice; Universities; Washington; Weight Gain; abeta accumulation; base; bench to bedside; cell type; clinically relevant; cognitive change; cohort; effective therapy; experimental study; human subject; imaging approach; improved; in vivo; insight; mortality; mouse model; neural network; neuron loss; neuropeptide Y; neurophysiology; novel; novel therapeutics; pre-clinical; prospective

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia in the elderly with currently no cure or effective disease-modifying therapy. The pathogenesis of AD is unclear; however, a leading hypothesis is that accumulation of amyloid-beta (Aβ) peptides derived from the amyloid precursor protein is one of the earliest pathological events resulting in neuronal dysfunction, at least in part by dysregulating intracellular Ca2+ homeostasis, and disruption of neural networks culminating in dementia. While cognitive impairment is the major manifestation of AD, non-cognitive manifestations such as unintentional body weight loss often occurs prior to the cognitive decline. Furthermore, weight loss in AD correlates with worsening disease progression and increased mortality, while weight gain is protective. Collectively, this suggests that brain regions such as the hypothalamus that regulate body weight and systemic metabolism may be selectively vulnerable to Aβ early in the pathogenesis of AD during the presymptomatic or preclinical stages. However, the cellular and molecular mechanisms underlying the early systemic metabolic dysfunction in AD have remain largely unexplored. Therefore, the goal of this application is to test the hypothesis that hypothalamic networks regulating systemic metabolism are selectively vulnerable to Aβ pathology and contribute to the early pathogenesis of AD. We will use a “bench-to-bedside” strategy using state-of-the-art molecular, neurophysiological, imaging, and genomic approaches in genetic mouse models, and verify key findings in clinically relevant human studies. We will test the following working hypotheses: (a) disruption of intracellular Ca2+ homeostasis by Aβ is an early pathological event leading to dysfunction of leptin-responsive hypothalamic NPY/AgRP neurons; (b) Aβ causes disruption of hypothalamic networks regulating systemic metabolism; and (c) central leptin signaling dysfunction is an early manifestation of human subjects with Alzheimer’s disease. The findings from this project will shed light on the mechanisms underlying early selective vulnerability in the hypothalamic network regulating systemic metabolism and identify the cell types affected, thereby filling a knowledge gap in our understanding of one of the earliest clinical manifestations of AD.

项目总结/摘要 阿尔茨海默病（AD）是老年痴呆症最常见的原因，目前没有治愈或有效的治疗方法。 疾病缓解疗法AD的发病机制尚不清楚;然而，一个主要的假设是， 来源于淀粉样前体蛋白的淀粉样β（Aβ）肽的积累是最早的 导致神经元功能障碍的病理事件，至少部分通过细胞内Ca 2+失调 稳态和神经网络的破坏最终导致痴呆。虽然认知障碍是 在AD的临床表现中，非认知表现如无意的体重减轻通常发生在 认知能力下降此外，AD中的体重减轻与疾病进展恶化相关， 增加死亡率，而体重增加是保护性的。总的来说，这表明大脑区域，如 调节体重和全身代谢下丘脑可能在早期选择性地对Aβ敏感， AD在症状前或临床前阶段的发病机制。然而，细胞和分子 AD中早期全身代谢功能障碍的潜在机制在很大程度上仍未被探索。 因此，本申请的目标是测试下丘脑网络调节全身性神经元的假设。 代谢选择性地易受Aβ病理的影响，并有助于AD的早期发病机制。我们将 使用“从实验室到床边”的策略，使用最先进的分子、神经生理学、成像和基因组学技术， 在遗传小鼠模型中的方法，并在临床相关的人类研究中验证关键发现。我们将测试 以下工作假设：（a）Aβ破坏细胞内Ca 2+稳态是一种早期病理性 导致瘦素反应性下丘脑NPY/AgRP神经元功能障碍的事件;（B）Aβ导致下丘脑NPY/AgRP神经元功能障碍的事件; 调节全身代谢的下丘脑网络;和（c）中枢瘦素信号传导功能障碍是一种早期的 这是患有阿尔茨海默病的人类受试者的表现。该项目的研究结果将揭示 下丘脑网络调节全身代谢的早期选择性脆弱性机制 并确定受影响的细胞类型，从而填补了我们对最早的一种 AD的临床表现。