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

Abstract

We recently identified a novel amyloid precursor protein mutation (E693Δ) in familial Alzheimer's-type dementia. This mutation produces amyloid-β (Aβ) variant lacking glutamate-22 (E22Δ), which showed enhanced oligomerization but no fibrillization. Here, we examined in-vitro toxicity of Aβ E22Δ peptide. Wild-type Aβ1-42 showed a dose-dependent (1 nM to 1 μM) cytotoxicity to cultured neuronal cells in the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay, whereas Aβ1-42 E22Δ was toxic only weakly at 1 μM. In mouse hippocampal slices, however, Aβ1-42 E22Δ caused a dose-dependent (0.1–10 μM) decrease of synaptophysin, whereas wild-type Aβ1-42 was trophic at 0.1–1 μM and toxic at 10 μM. These results suggest that extracellular Aβ E22Δ causes more potent synaptic alteration, but lower neurodegeneration, than wild-type Aβ probably because of its unique aggregation property.