Hypothalamic and metabolic dysfunction in Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是老年人痴呆症最常见的原因，目前还没有治愈或有效的方法 疾病修正疗法。阿尔茨海默病的发病机制尚不清楚；然而，一个主要的假说是 由淀粉样前体蛋白衍生的淀粉样β蛋白(Aβ)多肽的积累是最早的 导致神经元功能障碍的病理事件，至少部分是通过细胞内钙离子调节失调 动态平衡和神经网络的破坏最终导致痴呆症。虽然认知障碍是主要的 阿尔茨海默病的表现，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，阿尔茨海默病的体重减轻与病情恶化和 增加死亡率，而体重增加是有保护作用的。总体而言，这表明大脑区域，如 调节体重和系统代谢的下丘脑在早期可能选择性地易受β的影响 阿尔茨海默病症状前或临床前期的发病机制。然而，细胞和分子 阿尔茨海默病早期全身性代谢功能障碍的机制在很大程度上仍不清楚。 因此，这一应用的目标是检验下丘脑网络调节全身性 代谢选择性地易受Aβ病理的影响，参与了AD的早期发病。我们会 利用最先进的分子、神经生理学、成像和基因组技术，采用“从床到床”的策略 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)β破坏细胞内钙稳态是一种早期的病理现象 导致瘦素反应的下丘脑NPY/AgRP神经元功能障碍的事件；(B)β导致 下丘脑调节系统代谢的网络；和(C)中枢瘦素信号功能障碍是早期 阿尔茨海默病患者的临床表现。这个项目的发现将有助于揭示 调节系统代谢的下丘脑网络早期选择性易损性的机制 并确定受影响的细胞类型，从而填补了我们在认识上最早的一个空白 阿尔茨海默病的临床表现。

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.