Amyloid-beta E22Delta variant induces synaptic alteration in mouse hippocampal slices.
We recently identified a novel amyloid precursor protein mutation (E693Delta) in familial Alzheimer's-type dementia. This mutation produces amyloid-beta (Abeta) variant lacking glutamate-22 (E22Delta), which showed enhanced oligomerization but no fibrillization. Here, we examined in-vitro toxicity of Abeta E22Delta peptide. Wild-type Abeta1-42 showed a dose-dependent (1 nM to 1 microM) cytotoxicity to cultured neuronal cells in the 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide assay, whereas Abeta1-42 E22Delta was toxic only weakly at 1 microM. In mouse hippocampal slices, however, Abeta1-42 E22Delta caused a dose-dependent (0.1-10 microM) decrease of synaptophysin, whereas wild-type Abeta1-42 was trophic at 0.1-1 microM and toxic at 10 microM. These results suggest that extracellular Abeta E22Delta causes more potent synaptic alteration, but lower neurodegeneration, than wild-type Abeta probably because of its unique aggregation property.
Takuma
Hiroshi
H
Department of Neuroscience, Osaka City University Graduate School of Medicine, Osaka, Japan.
Teraoka
Rie
R
Mori
Hiroshi
H
Tomiyama
Takami
T
D016229:Amyloid beta-Peptides / Q000235:genetics / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D009924:Organ Culture Techniques; D010446:Peptide Fragments; D013569:Synapses / Q000187:drug effects* / Q000473:pathology; D016708:Synaptophysin / Q000096:biosynthesis / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D016708:Synaptophysin