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

项目总结 慢性应激日益被认为是散发性AD的危险因素。失调症 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，慢性应激暴露加剧Aβ和tau 病理和认知功能衰退。位于弓状核的AgRP神经元共同表达GABA和 广泛投射到下丘脑室旁核。我们最近的研究表明 慢性应激降低AgRP神经元的放电频率，刺激AgRP神经元可以逆转慢性应激 压力导致的行为缺陷，包括记忆障碍。HPA对压力的反应也可以是 通过刺激AgRP神经元而受到抑制。此外，我们提供了新的初步数据，表明老龄化 诱导AgRP神经元沉默。我们假设慢性压力和衰老共同导致AgRP沉默。 神经元，这导致对下丘脑室旁核的抑制性输入减少。这削弱了负面反馈，并推动了HPA 多动症，进而加速大脑衰老，加重AD的病理。为了检验这一假设，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神经元活动参与下丘脑轴的过度刺激和应激加剧的Aβ和tau 病理学。在目标3中，我们将确定AGE诱导的AgRP神经元沉默是否加速了 Aβ积聚的进展与认知功能下降。

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.