Role of AgRP neurons in chronic stress-accelerated brain aging and progression of Alzheimer's disease

AgRP 神经元在慢性应激加速的大脑衰老和阿尔茨海默病进展中的作用

• 批准号: 10740580
• 负责人: Xin-Yun Lu
• 金额: $ 68.49万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740580
• 关键词: Abeta synthesis; Acceleration; Accounting; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Behavior; Behavioral; Brain; Brain region; Cells; Chronic; Chronic stress; Cognitive; Corticotropin-Releasing Hormone; Data; Deacetylase; Dementia; Disease Progression; Down-Regulation; Exposure to; Feedback; Glucocorticoid Receptor; Glucocorticoids; Goals; Hydrocortisone; Hyperactivity; Hypothalamic structure; Impaired cognition; Knock-in Mouse; Memory Loss; Memory impairment; Molecular; Molecular Target; Mus; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Pathogenesis; Pathology; Phenotype; Population; Potassium; Predisposition; Production; Regulation; Research; Resistance; Risk Factors; Role; SIRT1 gene; Senile Plaques; Stress; Structure of nucleus infundibularis hypothalami; Testing; abeta accumulation; abeta deposition; age related; age related neurodegeneration; aging brain; biological adaptation to stress; gamma-Aminobutyric Acid; hyperphosphorylated tau; hypothalamic-pituitary-adrenal axis; interest; neural; neuropathology; novel; overexpression; paraventricular nucleus; response; restraint stress; social; tau Proteins; transcriptome

PROJECT SUMMARY Chronic stress is increasingly being recognized as a risk factor for sporadic AD. Dysregulation of the hypothalamic–pituitary–adrenal axis (HPA axis) is common in AD patients. By stimulating corticotropin-releasing hormone (CRH) expression and glucocorticoid secretion, chronic stress exposure exacerbates Aβ and tau pathologies and cognitive decline. AgRP neurons, located in the arcuate nucleus, co-express GABA and send extensive projections to the paraventricular nucleus of the hypothalamus. Our recent studies have shown that chronic stress decreases firing rates of AgRP neurons, and that stimulating AgRP neurons can reverse chronic stress-induced behavioral deficits, including memory impairment. HPA responses to stress can also be dampened by stimulating AgRP neurons. In addition, we provide novel preliminary data showing that aging induces silencing of AgRP neurons. We hypothesize that chronic stress and aging converge to silence AgRP neurons, which leads to reduced inhibitory inputs to the PVN. This weakens negative feedback and drives HPA hyperactivity, which in turn accelerates brain aging and worsens AD pathologies. To test this hypothesis, we propose three specific aims. In Aim 1, we will identify molecular mechanisms of chronic stress- and aging- induced silencing of AgRP neurons. In Aim 2, we will determine whether chronic stress-induced inhibition of AgRP neuron activity contributes to overstimulation of the HPA axis and stress-exacerbated Aβ and tau pathologies. In Aim 3, we will determine whether age-induced silencing of AgRP neurons accelerates the progression of Aβ accumulation and cognitive decline.

项目摘要 慢性压力越来越多地被认为是散发性AD的危险因素。失调 下丘脑-垂体-肾上腺轴（HPA轴）在AD患者中较为常见。通过刺激促肾上腺皮质激素释放 激素（CRH）表达和糖皮质激素分泌，慢性应激暴露加重Aβ和tau蛋白 病理和认知能力下降。位于弓状核内的AgRP神经元共表达GABA， 下丘脑室旁核的广泛投射。我们最近的研究表明， 慢性应激降低了AgRP神经元的放电率，刺激AgRP神经元可以逆转慢性应激。 压力引起的行为缺陷，包括记忆障碍。HPA对压力的反应也可能是 通过刺激AgRP神经元来抑制。此外，我们还提供了新的初步数据，表明衰老 诱导AgRP神经元沉默。我们假设慢性压力和衰老会使AgRP沉默 神经元，这导致对PVN的抑制性输入减少。这削弱了负反馈，并推动HPA 过度活跃，这反过来又加速了大脑老化和AD病理。为了验证这个假设，我们 提出三个具体目标。在目标1中，我们将确定慢性压力和衰老的分子机制， 诱导AgRP神经元沉默。在目标2中，我们将确定慢性应激诱导的抑制是否 AgRP神经元活动有助于HPA轴的过度刺激和应激加重的Aβ和tau蛋白 病理学在目标3中，我们将确定年龄诱导的AgRP神经元沉默是否加速了神经元的衰老。 Aβ蓄积和认知能力下降的进展。