Early memory deficits precede plaque deposition in APPswe/PS1dE9 mice: Involvement of oxidative stress and cholinergic dysfunction

A large body of evidence has shown that cognitive deficits occur early, before amyloid plaque deposition, suggesting that soluble amyloid-beta protein (A beta) contributes to the development of early cognitive dysfunction in Alzheimer disease (AD). However, the underlying mechanism(s) through which soluble A beta exerts its neurotoxicity responsible for cognitive dysfunction in the early stage of AD remains unclear so far. In this study, we used preplaque APPswe/PS1dE9 mice ages 2.5 and 3.5 months to examine alterations in cognitive function, oxidative stress, and cholinergic function. We found that only soluble A beta, not insoluble A beta, was detected in these preplaque APPswe/PS1dE9 mice. APPswe/PS1dE9 mice 2.5 months of age did not show any significant changes in the measures of cognitive function, oxidative stress, and cholinergic function, whereas 3.5-month-old APPswe/PS1dE9 mice exhibited spatial memory impairment in the Morris water maze, accompanied by significantly decreased acetylcholine (ACh), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-px) as well as increased malondialdehyde (MDA) and protein carbonyls. In 3.5-month-old preplaque APPswe/PS1dE9 mice, correlational analyses revealed that the performance of impaired spatial memory was inversely correlated with soluble A beta MDA, and protein carbonyls, as well as being positively correlated with ACh, ChAT, SOD, and GSH-px; soluble A beta level was inversely correlated with ACh, ChAT, SOD, and GSH-px, as well as being positively correlated with MDA and protein carbonyls; ACh level showed a significant positive correlation with ChAT, SOD, and GSH-px, as well as a significant inverse correlation with MDA and protein carbonyls. Collectively, this study provides direct evidence that increased oxidative damage and cholinergic dysfunction may be early pathological responses to soluble A beta, and involved in early memory deficits in the preplaque stage of AD. These findings suggest that early antioxidant therapy and improving cholinergic function may be a promising strategy to prevent or delay the onset and progression of AD. (C) 2012 Elsevier Inc. All rights reserved.