mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1

Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Aβ are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region. Background Three loci have been identified that account for nearly all the familial Alzheimer's disease (AD) cases. Mutations in the amyloid precursor protein (APP) gene account for around 2-3% percent of familial AD cases and mutations in presenilins 1 and 2 (PS1 and PS2) have been linked to 70-80% of early onset AD [1-3]. The mutations associated with early onset familial AD in a Swedish family, where the 695 amino acid APP protein contains the two mutations K670N and M671L (APP695SWE mutation), affect