Chronic Psychosocial Stress Accelerates Impairment of Long-Term Memory and Late-Phase Long-Term Potentiation in an At-Risk Model of Alzheimer's Disease

Although it is generally agreed that A beta contributes to the pathogenesis of AD, its precise role in AD and the reason for the varying intensity and time of onset of the disease have not been elucidated. In addition to genetic factors, environmental issues such as stress may also play a critical role in the etiology of AD. This study examined the effect of chronic psychosocial stress in an at-risk (treatment with a sub-pathogenic dose of A beta; subA beta) rat model of AD on long-term memory by three techniques: memory tests in the radial arm water maze, electrophysiological recordings of synaptic plasticity in anesthetized rats, and immunoblot analysis of learning-and long-term memory-related signaling molecules. Chronic psychosocial stress was induced using a rat intruder model. The subA beta rat model of AD was induced by continuous infusion of 160 pmol/day A beta(1-42) via a 14-day i.c.v. osmotic pump. All tests showed that subA beta rats were not different from control rats. Result from behavioral tests and electrophysiological recordings showed that infusion of subA beta in chronically stressed rats (stress/subA beta group) caused significant impairment of cognitive functions and late-phase long-term potentiation (L-LTP). Molecular analysis of various signaling molecules after expression of L-LTP, revealed an increase in the levels of p-CREB in control, stress, and subA beta rats, but not in the stress/subA beta rats. These findings suggest that the chronic stress-induced molecular alteration may accelerate the impairment of cognition and synaptic plasticity in individuals at-risk for AD. (C) 2010 Wiley-Liss, Inc.