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

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.