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

Behavioural brain research

PubMedID: 21513747

Zhang W, Hao J, Liu R, Zhang Z, Lei G, Su C, Miao J, Li Z. Soluble Aß levels correlate with cognitive deficits in the 12-month-old APPswe/PS1dE9 mouse model of Alzheimer's disease. Behav Brain Res. 2011;222(2):342-50.
Amyloid-beta peptide (Aß) 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 Aß pathology is responsible for the cognitive deficits in AD. In the present study, the cognitive deficits and the profiles of Aß 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 Aß1-40 and Aß1-42 levels were highly correlated with spatial learning deficits and long-term contextual memory deficits, as well as cortical and hippocampal soluble Aß1-40 and Aß1-42 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 Aß plaque load and fibrillar Aß plaque load), total Aß levels (Aß1-40 and Aß1-42), as well as insoluble Aß levels (Aß1-40 and Aß1-42). Stepwise multiple regression analysis identified hippocampal soluble Aß1-40 and Aß1-42 levels as independent factors for predicting the spatial learning deficits and the long-term contextual memory deficits, as well as hippocampal and cortical soluble Aß1-40 and Aß1-42 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 Aß in middle-aged APPswe/PS1dE9 mice, in which soluble Aß levels are only a tiny fraction of the amount of total Aß levels. Consequently, our findings provide further evidence that soluble Aß might primarily contribute to cognitive deficits in AD, suggesting that reducing the levels of soluble Aß species would be a therapeutic intervention for AD patients even with large deposits of aggregated, insoluble Aß.