ABSENCE OF CENTRAL CHOLINERGIC DEFICITS IN APOE KNOCKOUT MICE

ApolipoproteinE (ApoE) genotype has recently been identified as a majo r risk factor for Alzheimer's disease (AD) but the mechanism(s) by whi ch ApoE isoforms influence this disease remain unclear. Recent studies suggest that mice deficient in ApoE may exhibit impaired central chol inergic function. Since this neurotransmitter system has traditionally been associated with the pathogenesis of AD, we have further investig ated the impact of ApoE gene deletion on this system. Female ApoE knoc kout (ko) mice, age 12 months, were compared with wild type littermate controls using a range of behavioural, biochemical and histochemical techniques. Pre-treatment with the cholinomimetic, donepezil (E2020; 2 .5-5 mg kg(-1) IF), produced significant hypothermia and induction of tremor in both wild type and ApoE ko mice. The magnitude of change did not significantly differ between the groups. Cognitive testing in the Morris water maze revealed that both wild type and ApoE ko mice could learn the location of a hidden escape platform with similar rates of acquisition and accuracy. Similarly, the behaviour of both genotypes p roved indistinguishable in a Y-maze spontaneous alternation procedure. The protocols used for both cognitive tests were then shown to be sen sitive to the disruptive effects of scopolamine (but not scopolamine m ethyl bromide). Following behavioural testing, choline acetyltransfera se (ChAT) activity was measured in the hippocampus, frontal and entorh inal cortex and striatum. In each case there was no difference between the genotypes. In addition, coronal sections of striatum and anterior hippocampal regions of ApoE ko and wild type mice showed similar patt erns of acetylcholinesterase (AChE) staining, with no qualitative or o bvious quantitative difference. Finally, analysis of plasma cholestero l levels confirmed ApoE genotype. In conclusion, using a combination o f behavioural, histochemical and biochemical measurements, we have fai led to detect any significant differences in central cholinergic activ ity between wild type and ApoE ko mice.