Soluble Aβ levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease

Amyloid-beta peptide (A beta) is believed to be central in the pathogenesis of Alzheimer's disease (AD) characterized by cognitive deficits. However, it remains uncertain which form(s) of A beta pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of A beta pathology were characterized in the 12-month-old APPswe/PS1dE9 double transgenic mice, and their correlations were examined. Compared with non-transgenic littermates, the middle-aged APPswe/PS1dE9 mice exhibited spatial learning and memory deficits in the water maze test and long-term contextual memory deficits in the step-down passive avoidance test. Among the middle-aged APPswe/PS1dE9 mice, hippocampal soluble A beta 1-40 and A beta 1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble A beta 1-40 and A beta 1-42 levels were strongly correlated with spatial memory deficits. By contrast, no significant correlations were observed between three measures of cognitive functions and amyloid plaque burden (total A beta plaque load and fibrillar A beta plaque load), total A beta levels (A beta 1-40 and A beta 1-42), as well as insoluble A beta levels (A beta 1-40 and A beta 1-42). Stepwise multiple regression analysis identified hippocampal soluble A beta 1-40 and A beta 1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble A beta 1-40 and A beta 1-42 levels as independent factors for predicting the spatial memory deficits in transgenic mice. These results demonstrate that cognitive deficits are highly related to the levels of soluble A beta in middle-aged APPswe/PS1dE9 mice, in which soluble A beta levels are only a tiny fraction of the amount of total A beta levels. Consequently, our findings provide further evidence that soluble A beta might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble A beta species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble A beta. (C) 2011 Elsevier B.V. All rights reserved.