UC San Diego

Alzheimer’s Disease (AD) is the most common form of dementia. Chronic stress has been suggested to influence the progression of AD. Moreover, corticotropin-releasing factor (CRF) signaling in AD has been shown to be upregulated by stress and influence AD pathology such as amyloid-beta (Aβ) accumulation. In rodent models, similar AD-related pathology and cognitive impairments are produced when exposed to either stress or exogenous CRF. Previous studies have shown that PSAPP (AD) mice treated with CRFR1 antagonist (R121919) resulted in reduced Aβ accumulation and improvements in behavioral tests. However, the influence of stress while underdoing drug treatment is unknown. In this comparison study, we subjected cohorts of AD mice to R121919 in the presence and absence of restraint stress treatment. AD mice were aged to 6 and 12 months to investigate the pre-clinical and mature timepoints of AD pathology. Daily drug/vehicle treatment began at 2 months of age. Stress for the 6 and 12-month groups started at 2 and 6 months, respectively. Overall, R121919 treated AD mice resulted in a significant reduction of Aβ levels. Additionally, it was shown that chronic restraint stress exacerbated Aβ levels. This study suggests that CRFR1 antagonist treatment provides a potential preventative and disease-modifying therapy for populations subjugated to stress and at risk for AD development. Our data provides an important relationship between stress signaling in the CNS and the neuropathology of AD.