Corticotrophin-Releasing Factor Receptor 1 and chronic stress in Alzheimer’s Disease pathogenesis.
Chronic stress not only decreases the quality of life, but also increases the risk of developing a stress-related neuropsychiatric disorder, cardiovascular diseases, metabolic dysfunction, and/or Alzheimer’s disease (AD). Through animal studies, a key stress signaling factor in the hypothalamic-pituitary-adrenal (HPA) axis, corticotropin-releasing factor (CRF), was found to contribute to the development of AD through binding to its cognate type-1 receptor (CRFR1). The two defining cellular pathological phenotypes in AD, amyloid-β (Aβ) plaques and hyperphosphorylated tau (p-tau) tangles are both potentiated by CRFR1 activation. Current treatments for AD offer only a temporary reprieve from symptoms and do not provide ample relief. Unfortunately, the recent experimental therapies targeting amyloidogenic pathways have been unsuccessful in the treatment of human AD. Delineating the therapeutic potential of drugs targeting the CRF system could provide a novel treatment approach to combat AD pathogenesis.To assess how CRFR1-antagonism (vehicle/R121919) and/or stress alters AD pathology, early and mature (6- and 12- month) Wt/PSAPP cohorts were subjected to a series of behavioral assays (measuring learning, memory, and cognitive rigidity), immunohistochemical imaging and analysis of Aβ plaques in cortical/hippocampal sections, and biochemically probed for soluble/insoluble Aβ species in cortical fractions. Early R121919 treatment reduces AD pathology: improving behavioral task ability, reducing plaques throughout the hippocampus and cortex, and lowering cortical highly toxic soluble Aβ oligomers while increasing the amount of in-soluble monomeric Aβ species. Interestingly, stress improves memory, increases hippocampal plaques, lowers cortical plaques, and increases the amount of cortical insoluble monomeric species of Aβ, in early vehicle groups. While early treatment with R121919 ameliorates AD pathogenesis, mature AD pathology was not affected by R121919 (treatment did lower mature cortical soluble monomeric Aβ species). Parallel to these studies, stress did not alter mature behavioral deficits, but did lower hippocampal and cortical plaques, while increasing levels of mature cortical highly neurotoxic soluble oligomeric Aβ species (vehicle-cohorts) and mature cortical soluble monomeric Aβ (R121919-cohorts). Overall, CRFR1-antagonism may provide novel therapies for AD pathogenesis.