Validation Studies of CRF Receptor 1 as a Target for AD

Abstract

Alzheimer's disease (AD) is the most common form of dementia and is defined by two neuropathologic hallmarks: senile plaques and neurofibrillary tangles, respectively composed of β‐amyloid (Aβ) and phosphorylated tau protein. Very few incidences of AD are developed from genetic mutations. A majority of cases arise sporadically, and are thought to result from the interplay of genetic and environmental factors. Corticotropin‐releasing factor (CRF) signaling in AD, when exacerbated by stress, has been shown to influence AD pathology. With an aging population of veterans and individuals with stress‐related neuropsychiatric disorders (i.e. PTSD, depression, anxiety, etc.), uncovering the link between this stress pathway and AD pathogenesis can help to develop therapeutics to relieve the emotional and economic burden created by AD. Rodent models of this disease have found that stress exposure and CRF signaling are linked to the pathogenesis of AD. In this study, we explored whether therapeutic targets that modulate the CRF system (i.e. the CRFR1‐selective antagonist R121919) could impact the behavioral and pathological endpoints seen in AD mice. AD mice (PSAPP) were aged to 6 and 12 months in the presence or absence of restraint stress and/or R121919. Drug‐treated PSAPP mice had significantly reduced Aβ levels, plaque accumulation, and cognitive impartment, relative to the control cohorts. Collectively, our data provide evidence that CRFR1 modulation may be mechanistically linked to the neuropathogenesis of AD.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.