Chronic Psychosocial Stress Exacerbates Impairment of Cognition and Long-Term Potentiation in β-Amyloid Rat Model of Alzheimer's Disease

doi:10.1016/j.biopsych.2008.08.021

Biological Psychiatry

Volume 65, Issue 11, 1 June 2009, Pages 918-926

https://doi.org/10.1016/j.biopsych.2008.08.021 Get rights and content

Background

Alzheimer's disease (AD) is a degenerative disorder that leads to progressive cognitive decline. Alzheimer's disease develops as a result of over-production and aggregation of β-amyloid (Aβ) peptides in the brain. The reason for variation in the gravity of symptoms among AD patients is unknown and might result from patient-related factors including lifestyle. Individuals suffering from chronic stress are at an increased risk for developing AD. This study investigated the effect of chronic psychosocial stress in Aβ rat model of AD.

Methods

Psychosocial stress was induced with a rat intruder model. The rat model of AD was induced by 14-day osmotic pump infusion of a mixture of 300 pmol/day Aβ_1-40/Aβ_1-42. The effect of chronic stress on the severity of Aβ-induced spatial learning and memory impairment was tested by three approaches: behavioral testing in the radial arm water maze, in vivo electrophysiological recording in anesthetized rat, and immunoblot analysis to determine protein levels of learning- and memory-related molecules.

Results

A marked impairment of learning and memory developed when stress was combined with Aβ, more so than that caused by Aβ alone. Additionally, there was a significantly greater impairment of early-phase long-term potentiation (E-LTP) in chronically stressed/Aβ-treated rats than in either the stressed or Aβ-treated rats. This might be a manifestation of the reduction in protein levels of calcium/calmodulin-dependent protein kinase II (CaMKII) and the abnormal increase in calcineurin levels.

Conclusions

Chronic stress significantly intensified Aβ-induced deficits of short-term memory and E-LTP by a mechanism involving decreased CaMKII activation along with increased calcineurin levels.

Section snippets

Animals and Housing Conditions

We used adult male Wistar rats, weighing 200–225 g at the beginning of the experiment (Charles River Laboratories, Wilmington, Massachusetts). Six rats were housed/cage in a climate-controlled room (25°C) with ad libitum food and water, under a 12-hour light/dark cycle (light on at 7:00 am). Experiments were carried out between 9:00 am and 5:00 pm. All animal procedures were carried out in accordance with the National Research Council's Guide for The Care and Use of Laboratory Animals and on

Chronic Stress Exacerbates Aβ Deficits in Spatial Learning

On days 1–2 of the RAWM training, control, stress, and Aβ animals learned the location of the hidden platform at equivalent rates, as indicated by the decreasing number of errors made from trials 1–4 (Figure 1A). However, stress/Aβ rats learned slower than all other groups (Figure 1A). By contrast, on days 6–8, although stress/Aβ and Aβ groups showed some improvement in learning abilities, their learning ability remained significantly different from each other as well as from control and stress

Discussion

The present study evaluated the effect of chronic stress on the severity of Aβ-induced cognitive deficits. The results of our behavioral, electrophysiological, and molecular experiments indicated that prior and concomitant exposure of Aβ-infused rats to 6 weeks of chronic psychosocial stress intensified the severity of Aβ-induced cognitive deficits and synaptic dysfunction. Under our experimental conditions, chronic infusion of 300 pmol/day Aβ_1-40/Aβ_1-42 mixture induced deficits in learning and

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Archival ReportChronic Psychosocial Stress Exacerbates Impairment of Cognition and Long-Term Potentiation in β-Amyloid Rat Model of Alzheimer's Disease

Background

Methods

Results

Conclusions

Section snippets

Animals and Housing Conditions

Chronic Stress Exacerbates Aβ Deficits in Spatial Learning

Discussion

Neurosci Lett

Neuron

Metabolism

Biol Psychiatry

Behav Brain Res

Trends Pharmacol Sci

Physiol Behav

Neurobiol Dis

Brain Res

Bioorg Med Chem Lett

Mech Ageing Dev

Neurobiol Dis

Biochem Biophys Res Commun

Exp Neurol

Brain Res

Jpn J Pharmacol

Brain Res

Brain Res

Neurosci Lett

Cell

Biophys J

Neurochem Int

Neuroscience

Neuroscience

Neurobiol Learn Mem

Neuroscience

J Biol Chem

Biol Psychiatry

Science, medicine and the future: Alzheimer's disease

BMJ

Alzheimer neurofibrillary degeneration: Significance, etiopathogenesis, therapeutics and prevention

J Cell Mol Med

The synaptic Abeta hypothesis of Alzheimer disease

Nat Neurosci

Alzheimer's disease is a synaptic failure

Science

Synaptic plasticity in animal models of early Alzheimer's disease

Philos Trans R Soc Lond B Biol Sci

Behavioral stress modifies hippocampal plasticity through N-methyl-D-aspartate receptor activation

Proc Natl Acad Sci U S A

Biology of posttraumatic stress disorder

J Clin Psychiatry

Stress and hippocampal plasticity

Annu Rev Neurosci

Archival Report
Chronic Psychosocial Stress Exacerbates Impairment of Cognition and Long-Term Potentiation in β-Amyloid Rat Model of Alzheimer's Disease