Timing impairments in early Alzheimer's disease: Evidence from a mouse model

A key characteristic of Alzheimer's disease (AD) is loss of episodic memory-memory for what happened, where and when; this final aspect-timing-is the focus of the present article. Although timing deficits have been reported in AD patients, few parallel studies have been performed in animals, compromising the translational potential of these findings. We looked for timing impairments in the APPswe/PS1dE9 mouse model of AD at 4-5 months of age, before significant plaques have developed. In Experiments 1 and 2a mice were trained with auditory stimuli that were followed by food, either immediately (delay stimulus; Experiments 1 and 2a) or after a short interval (trace stimulus; Experiment 1). In Experiment 1 APPswe/PS1dEdE9 mice conditioned normally, but showed more variable timing of the delay-conditioned cue. Experiment 2 examined timing of two delay-conditioned CSs, with Experiment 2a using mice 4-5 months old, and Experiment 2b mice at 6-8 months. With the longer conditional stimulus (CS) the transgenic mice showed both more variable timing and earlier timed peak responding than wild-type mice; these effects were not influenced by age. Our results bear similarity to those seen in AD patients, raising the possibility that they have diagnostic potential. They also resemble deficits in animals with dorsal hippocampal lesions, suggesting that they could be mediated by this area. Activated microglia, a component of the immune response thought to be driven by the elevated levels of β-amyloid, were elevated in both dentate gyrus and striatum of young transgenic mice, providing some support for this proposal. (PsycINFO Database Record (c) 2020 APA, all rights reserved).