A detailed analysis of the early context extinction deficits seen in APPswe/PS1dE9 female mice and their relevance to preclinical Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an incurable age-related neurodegenerative condition, characterised by progressive decline in cognitive and physical functions, and extensive brain damage. Identifying cognitive deficits that accompany early AD is critical, as the accompanying synaptic changes can be effectively targeted by current treatments - at present AD is typically not diagnosed until brain pathology is established, and treatment relatively ineffective. We therefore examined early cognitive changes in 4-month-old mice over-expressing 2 genes responsible for AD (APPswe/PS1d9 mouse line). Experiment 1 tested 4-month-old female APPswe/PS1dE9 mice and their wild-type littermates on 4 validated tasks involving 8 cognitive and non cognitive measures. We observed a selective deficit in extinction of contextual fear in APPswe/PS1dE9 mice. To extend the generality of this finding, Experiment 2 examined conditioning and extinction of an auditory stimulus paired with a sucrose reinforcer. No effect of genotype was observed. A third experiment investigated whether the context extinction impairment could be attributed to an attentional deficit. One conditioning stimulus (CS) was preexposed without consequence, and then it and a second, novel auditory CS were paired with food. Preexposure produced equal retardation of conditioning of the preexposed CS in both genotypes. However, in Experiment 2, and marginally in Experiment 3, additional tests revealed evidence of a selective impairment in context extinction in transgenic mice. These data suggest that context extinction deficits precede other cognitive impairments in APPswe/PS1dE9 mice, an effect that has intriguing parallels with findings in patients with mild AD.