Detection of age-dependent working memory deterioration in APP751SL mice

Despite huge advances on Alzheimer's disease (AD) etiology, the clinical diagnosis remains the unique commonly used tool to detect the onset of the disease. For instance, epidemiological studies report that the combination of episodic and working memory disorders represents the most consistent sign of progression from mild cognitive impairment to AD. However, such working memory disorders failed to be observed early in transgenic mouse models of AD because the behavioral procedures used do not tackle properly crucial components of working memory. The aim of the present work was to assess early occurrence of working memory impairments in APP(751SL) mice. Therefore, we designed a new behavioral task in the water-maze, based on the principle of a delayed matching to place task, where spatial recognition was assessed for four different platform locations within a single session. First, we showed that dorsal hippocampal but not medial prefrontal cortex lesions in C57Bl6 mice induced a time-dependent impairment of spatial recognition. Then, the hippocampal-like memory alterations were reproduced in 7-8-month-old APP(751SL) mice but not in younger animals (5-6-month-old). We also demonstrated that these working memory deficits are related to progressive Aβ accumulation in the hippocampus, but not in the other selected brain structures.