Chronic Stress Accelerates and Intensifies Aβ-induced Alzheimer’s-disease-like Pathogenesis in Rat Models
Chronic Stress Accelerates and Intensifies Aβ-induced Alzheimer’s-disease-like Pathogenesis in Rat Models
US Neurology, 2010;6(1):32-5
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.
Keywords
Rat Alzheimer’s disease model, amyloid-beta, learning and memory, signaling molecules, synaptic plasticity
Disclosure: The author has no conflicts of interest to declare.
Received: February 24, 2010 Accepted: May 25, 2010 Citation: US Neurology, 2010;6(1):32–35
Correspondence: Karim A Alkadhi, PhD, Professor of Pharmacology, Department of PPS, College of Pharmacy, University of Houston, Houston, TX 77204-5037. E: kalkadhi@uh.edu
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by extracellular deposition of pathogenic amyloid-beta (Aβ) peptides, intracellular aggregation of hyperphosphorylated tau protein, and neuronal death.1,2 Molecular studies have shown that missense mutations in genes for amyloid precursor protein (APP), presenilin 1 (PS1), or presenilin 2 (PS2) account for the majority of familial AD cases.3,4 However, early-onset familial AD represents fewer than 5% of AD cases, while sporadic, late-onset AD is evident in over 95% of cases.3,4 The sporadic nature of AD suggests an environmental link that may trigger AD pathogenesis. In addition to its late onset, the variation in susceptibility to and time of onset of the disease suggests that, aside from genetic factors, environmental determinants such as chronic stress may also play a critical role in the etiology of sporadic AD. Additionally, during AD a progressive failure of synaptic transmission occurs; it begins as a localized decrease in synaptic function and over time progresses to global impairment of neurotransmission in the brain.5–7
Chronic stress is considered a negative modulator of the learning and memory process.8–12 Stress-induced intensification of cognitive impairment has been reported with various disorders including schizophrenia,13 Cushing’s disease,14 hypothyroidism,15 and AD.16,17 Clinical studies have shown elevated plasma cortisol levels in individuals with dementia and in AD patients.18–21 Accordingly, it has been postulated that stress may be associated with this disease.22–24 This is further supported by the epidemiological findings that individuals prone to experiencing psychological distress are more likely to develop mild cognitive impairment, or even AD, than non-stressed individuals.25,26 Clinical reports of hypercortism in AD patients18,27 and animal studies28,29 have shown that glucocorticoids participate in the regulation of APP levels, suggesting involvement of glucocorticoids in the pathogenesis of AD.
Exposure to stress activates the hypothalamic–pituitary–adrenal (HPA) axis, resulting in increased release of glucocorticoids into the bloodstream.30–32 The high level of glucocorticoids seen under stressful conditions is enough to activate type II glucocorticoid receptors, with negative consequences for hippocampal function.33,34 Thus, chronic stress can have a deleterious effect on hippocampal structure and function35 because of the abundance of glucocorticoid receptors in the hippocampus and its involvement in cognition.
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Rat Alzheimer’s disease model, amyloid-beta, learning and memory, signaling molecules, synaptic plasticity
