Chronic Stress Accelerates and Intensifies Aß-induced Alzheimer’s-disease-like Pathogenesis in Rat Models

Abstract

Apart from genetic factors, environmental factors such as stress may also play a critical role in the manifestation of Alzheimer’s disease (AD). We studied the impact of chronic psychosocial stress in two amyloid-beta (Aβ) rat models of AD by three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of long-term potentiation (LTP) in anesthetized rats, and immunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The first Aβ rat model, representing established AD, was induced by continuous intracerebroventricular (ICV) infusion of a pathogenic dose of Aβ peptides via a 14-day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, produced more depression of LTP, and accentuated the reduction of signaling molecule levels compared with the established model alone. The second model represents subjects that are clinically normal but are at risk for AD, and was induced by ICV infusion of a sub-threshold (sub-Aβ) dose of Aβ peptides. Chronic psychosocial stress was induced using a rat intruder model. Various tests showed that sub-Aβ rats were not significantly different from control rats. However, chronically stressed sub-Aβ rats showed more significant impairment of cognitive functions and early-phase LTP than that caused by stress alone. Molecular analysis revealed marked disturbances in the levels of essential signaling molecules in the stressed AD at-risk rats. These findings suggest that chronic stress may profoundly accelerate and intensify the impairment of cognition and synaptic plasticity in individuals at risk for AD and those with established AD, respectively. Possible mechanisms for the effect of chronic stress are discussed.