Year: 2008
Type: article
Abstract: Psychosocial stress has been suggested to be one of the environmental factors that can influence the pathogenesis of Alzheimer disease (AD). We previously showed that both behavioral stressors increased brain levels of A-beta in the Tg2576 mouse model of AD. Moreover, administration of exogenous corticotropin-releasing factor (CRF) mimicked the effects of stress on A-beta levels, perhaps by increasing levels of neuronal activity. In this study, we assessed the effects of corticotropin-releasing factor receptor-1 (CRFR1) antagonists on increases in A-beta induced by one week of isolation stress in the Tg2576 mouse, an animal model of AD. We conducted two experiments. In experiment 1, 14 Tg+ mice were randomly divided into 2 groups and exposed to either isolation or group-housing immediately after weaning for one week to determine if one-week of isolation stress would increase brain A-beta levels. In experiment 2, 41 Tg+ mice were randomly divided into 2 groups and exposed to either isolation or group-housing immediately after weaning for one week. Subgroups of these isolated and group-housed mice were injected daily with one of three CRFR1 antagonists – antalarmin (20mg/kg), R1211919.HCL (10mg/kg), LWH-63.HCL (20mg/kg), or vehicle (20%Tween 80) daily. Tissue A-beta levels were measured using an enzyme-linked immuno-sorbent assay (ELISA) in the hippocampus and overlying cortex. In experiment 1, there was a significant increase in A-beta levels (35–50%) [F(1,12)=5.495, p=0.003] in Tg+ mice exposed to one week of isolation stress. In experiment 2, factorial ANOVA indicated a significant overall effect of drug on A-beta levels [F(3,35)=8.153, p=0.0003], but no overall effect of housing condition [F(1,35)=0.657, p=0.467], nor an interaction between drug and housing condition [F(3,35)=2.226, p=0.102]. Post-hoc tests revealed that administration of antalarmin and R1211919.HCL significantly reduced A-beta levels in both isolated and group-housed mice as compared to LWH-63.HCL and vehicle (Ant vs LWH: p=0.018; Ant vs Vel: p=0.0028) (R121 vs LWH: p=0.0006; R121 vs Vel: p<0.0001). These results suggest that at least some CRFR1 antagonists may decrease A-beta levels independent of the presence of stressful housing conditions in a mouse model of AD.
Source: Alzheimer s & Dementia
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funder: National Institutes of Health
Award: G9000017712
OpenAlex ID: W2003679147