Chronic Stress Induce Learning And Memory Impairment In Old Mice And Its Related Mechanisms

Alzheimer’s disease (AD) is the major neurodegenerative disorder of the elderly, andis characterized by progressive cognitive deficits such as impairment of memory.Stress is an unavoidable condition of the human experience and includes both majorlife events and the problems of daily life, which both elevate the activities ofphysiological systems and disrupt homeostasis. One of the pathological hallmarks ofAD is extracellular accumulation of senile plaques composed primarily of aggregatedamyloid beta-protein (Aβ). Clinical data suggest that a stressful lifestyle can be a riskfactor for AD. Also, study showed that chronic stress could potentiate Aβ depositionand induces cognitive deficits in transgenic mouse models of AD, but whether chronicstress could potentiate Aβ deposition in non-transgenic mouse was seldom reported. Itis known that the onest of AD mainly happened in elders and Aβ increasedsignificantly with age in mouse, monkey, and human brains, therefore, it is valuable tostudy whether chronic stress could impair the cognition and its related mechanism inaged non-transgenic mouse.Objective: To determine whether chronic stress could potentiate learning and memoryimpairment in aged mice, and, if so, what the underlying mechanism is.Methods: Twenty male mice were divided randomly into control group and chronicstress group. Mice in stress group were exposed to one of the stressors including coldexposure, restraint, level shake and so on for two months. The ability of learning andmemory was determined by Morris water maze test, and the histopathologic changes of the hippocampus were examined under a light microscope. Serum corticosterone leveland the expression of amyloid beta-protein(Aβ1-40) were determined by Enzymelinked immunosorbent assay(ELISA), and Western blotting was performed todetermine the expression of β-site amyloid precursor protein-cleaving enzyme1(BACE1)and Aβ precursor protein (APP) in hippocampus of the brain. BACE activitywas assaied using fluorospectrophotometry.Results: Compared with the control group, the results showed that chronic stress couldincrease the escape latency and swimming distance during training session in theMorris water maze test in aged mice. The neuropathological changes werecharacterized by the decreased neuron number，soma shrinkage and condensation，ornuclear pyknosis in the CA3field of hippocampus in the stress group. On the otherhand, the expression of Aβ1-40, APP and BACE1protein in hippocampus wereincreased, as well as the serum corticosterone concentration in the stress group, butthere was no significant difference in BACE1activity between the chronic stress groupand control group.Conclusions: Chronic stress could induce learning and memory impairment andpathological damage in CA3field of the hippocampus in aged mice, which might berelated to chronic stress up-regulating the protein levels of Aβ1-40、APP and BACE1mediated by corticosterone.