Amyloid-β E22Δ variant induces synaptic alteration in mouse hippocampal slices

We recently identified a novel amyloid precursor protein mutation (E693 Delta) in familial Alzheimer's-type dementia. This mutation produces amyloid-beta (A beta) variant lacking glutamate-22 (E22 Delta), which showed enhanced oligomerization but no fibrillization. Here, we examined in-vitro toxicity of A beta E22 Delta peptide. Wild-type A beta 1-42 showed a dose-dependent (1 nM to 1 mu M) cytotoxicity to cultured neuronal cells in the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay, whereas A beta 1-42 E22 Delta was toxic only weakly at 1 mu M. In mouse hippocampal slices, however, A beta 1-42 E22 Delta caused a dose-dependent (0.1-10 mu M) decrease of synaptophysin, whereas wild-type A beta 1-42 was trophic at 0.1-1 mu M and toxic at 10 mu M. These results suggest that extracellular A beta E22 Delta causes more potent synaptic alteration, but lower neurodegeneration, than wild-type A beta probably because of its unique aggregation property.