|dc.description.abstract||Although it is generally accepted that Aβ contributes to the pathogenesis of Alzheimer's disease (AD), other factors that impact the severity and time of onset of the disease are not well known. Aside from genetic factors, environmental factors, such as stress, may also play a critical role in the manifestation of AD. Epidemiological studies indicate that individuals suffering from chronic stress are at an increased risk for developing AD. The present study investigated the effect of chronic psychosocial stress in an at-risk, subthreshold Aβ (subAβ) rat model of AD by three techniques: learning and memory tests in the radial arm water maze, electrophysiological recordings of long-term potentiation (LTP) and long-term depression (LTD) in anesthetized rats, and immunoblot analyses of learning- and memory-related signaling and AD-related molecules. Chronic psychosocial stress was induced using a rat intruder model. The subAβ rat model of AD was induced by continuous i.c.v. infusion of 160 pmol/day Aβ1-42 via a 14-day mini-osmotic pump.
Behavioral tests, electrophysiological recordings, and molecular analyses showed that subAβ rats were not significantly different from control rats, thus validating this model as an at-risk model of AD without phenotypic characteristics or cognitive deficits commonly associated with AD. However, chronically stressed subAβ-infused rats showed significantly greater impairment of cognitive functions and synaptic plasticity than that caused by stress alone. Molecular analyses of essential signaling molecules showed that animals subjected to stress have reduced basal levels of p-CaMKII, decreased p-CaMKII/CaMKII ratio, and increased basal levels of calcineurin. The infusion of subAβ into the cerebral ventricle of chronically stressed rats also decreased basal levels of p-CREB, total CREB and BDNF and increased basal levels of BACE. Furthermore, multiple high frequency stimulation failed to increase levels of p-CREB and BDNF during the late-phase of long-term potentiation. However, paired pulse stimulation produced a decrease in levels of BDNF during long-term depression in the stress/subAβ animals. Together, the results of our behavioral, electrophysiological, and molecular studies suggest that prior and concomitant exposure of subAβ-infused rats to chronic stress intensify the severity of stress-induced cognitive and synaptic plasticity deficits. Thus, chronic stress may accelerate the impairment of learning, memory, and synaptic plasticity in individuals “at-risk” for AD.||