The Ventromedial Hypothalamus Links Metabolism and Behavior in Alzheimer’s Disease
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PROJECT SUMMARY/ABSTRACT While progressive cognitive decline culminating in dementia is the most prominent clinical manifestation of Alzheimer’s disease (AD), non-cognitive manifestations including neuropsychiatric symptoms (e.g., agitation) and systemic metabolic deficits (e.g., unintentional body weight loss) are significant contributors to morbidity and mortality. Currently, these symptoms are often inadequately treated, leading to ineffective outcomes and potential side effects. Despite the clinical importance of managing agitation and body weight loss in AD, the underlying molecular mechanisms remain unclear. The ventromedial nucleus of the hypothalamus (VMH) has long been identified as a brain region critical for the regulation of agitation and systemic metabolism, suggesting that dysregulation of the VMH by pathogenic agents of AD such as amyloid-beta (Aβ) may be critical for the development of neuropsychiatric symptoms and systemic metabolic deficits in AD. However, whether dysregulation of the VMH contributes to the agitation and unintentional body weight loss and any underlying cellular mechanisms that may contribute to VMH dysfunction in AD are not known. Therefore, the goal of this application is to test the hypothesis that Aβ causes dysregulation of the VMH resulting in neuropsychiatric symptoms and systemic metabolic deficits in AD. We have assembled a multidisciplinary team with expertise in the VMH and clinical AD and will utilize molecular, genetic, and neurophysiological approaches in mouse models. We will test the following working hypotheses: (a) Aβ mediated VMH neuronal dysregulation causes the agitation and systemic metabolic deficits in AD; (b) Aβ causes dysfunction of specific neuronal populations within the VMH; (c) Aβ can directly cause hyperactivity of VMH neurons by modulating key calcium channels. The findings from this project will elucidate the mechanisms underlying key non-cognitive manifestations of AD and thereby identify potentially new therapeutic targets for these symptoms that currently have limited treatment options.
