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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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.

项目概要慢性压力越来越被认为是偶发性 AD 失调的危险因素。下丘脑-垂体-肾上腺轴（HPA 轴）在 AD 患者中很常见通过刺激促肾上腺皮质激素的释放。激素 (CRH) 表达和糖皮质激素分泌，慢性压力暴露会加剧 Aβ 和 tau 蛋白 AgRP 神经元位于弓状核，共同表达 GABA 并发送信号。我们最近的研究表明，对下丘脑室旁核的广泛投射。慢性应激会降低 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 HPA 对压力的反应也可能受到影响。通过刺激 AgRP 神经元来抑制此外，我们提供了新的初步数据表明衰老。诱导 AgRP 神经元沉默我们认为慢性压力和衰老会共同导致 AgRP 沉默。神经元，从而减少对 PVN 的抑制输入，从而削弱负反馈并驱动 HPA。过度活跃会加速大脑衰老并恶化 AD 病理。为了验证这一假设，我们进行了实验。在目标 1 中，我们将确定慢性压力和衰老的分子机制。在目标 2 中，我们将确定慢性应激是否会诱导 AgRP 神经元的抑制。 AgRP 神经元活动导致 HPA 轴过度刺激以及应激加剧的 Aβ 和 tau 蛋白在目标 3 中，我们将确定年龄引起的 AgRP 神经元沉默是否会加速 Aβ 积累和认知能力下降的进展。