Abstract
Environmental factors including chronic stress may play a critical role in the manifestation of Alzheimer’s disease (AD).This review summarizes our studies of the aggravation of the impaired cognitive ability and its cellular and molecular correlates by chronic psychosocial stress and prevention by nicotine in an Aβ rat model of AD. We utilized three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of the cellular correlates of memory, long-term potentiation (LTP) and long-term depression (LTD), in anesthetized rats, and immunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The Aβ rat model, representing the sporadic form of established AD, was induced by continuous i.c.v. infusion of a pathogenic dose of Aβ peptides via a 14- day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, accentuated the disruption of signaling molecules levels and produced greater depression of LTP than what was seen with Aβ infusion alone. Chronic treatment with nicotine was highly efficient in preventing the effects of Aβ infusion and the exacerbating impact of chronic stress. Possible mechanisms for the effect of chronic stress are discussed.
Highlights
Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative brain disorder characterized by extracellular accumulation of pathogenic amyloid-beta (A) 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 [3,4,5]
Based on findings from our model, we propose that decreasing calmodulin kinase II (CaMKII)-dependent protein phosphorylation may contribute to the mechanism by which chronic stress impairs memory and long-term potentiation (LTP) in this model of AD
Summary
Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative brain disorder characterized by extracellular accumulation of pathogenic amyloid-beta (A) peptides, intracellular aggregation of hyperphosphorylated tau protein, and neuronal death [1, 2]. Based on clinical reports of elevated plasma cortisol levels in individuals with dementia and in AD patients [22,23,24,25], it has been postulated that stress may be associated with this disease [26,27,28] Further support of this hypothesis comes from epidemiological findings that stressed individuals are more likely to develop mild cognitive impairment, or even AD, than non-stressed individuals [29, 30]. 588 Current Neuropharmacology, 2011, Vol 9, No 4 studies have shown that nicotine improves cognitive function in AD patients and attenuates A-induced amnesia in rodents [19, 40, 44, 45].The finding that chronic nicotine treatment prevents stress-induced down regulation of central nicotinic acetylcholine receptors (nAChRs) [46], suggests a mechanism by which nicotine may prevent stress-induced impairment of memory and LTP. The combined effects of psychosocial stress and nicotine in AD have not been studied thoroughly in any AD animal model; this review summarizes recent findings that are largely reported from this laboratory
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