Submicromolar Aβ42 reduces hippocampal glutamate receptors and presynaptic markers in an aggregation-dependent manner

摘要: Synaptic pathology in Alzheimer's disease brains is thought to involve soluble Aβ42 peptide. Here, sterile incubation PBS caused small oligomer formation as well heterogeneous, 6E10-immunopositive aggregates of 80-100kDa. The high molecular weight (H-agg) formed a time-dependent manner over an extended 30-day period. Interestingly, inverse relationship between dimeric and H-agg was more evident when incubations were performed at 37°C compared 23°C, thus providing experimental strategy with which address synaptic compromise produced by the different Aβ aggregates. species faster higher levels two aggregate preparations evaluated hippocampal slice cultures, sensitive system for monitoring integrity. Applied daily 80-600nM 7days, dose-dependent aggregation-dependent declines α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) N-methyl-d-aspartate (NMDA) receptor subunits presynaptic components. Unlike effects, induced only trace cellular degeneration that CA1 specific. preparation less effective decreasing markers, corresponding its reduced monomers dimers. dimers decayed significantly than rapidly either temperature. These findings indicate can self-aggregate into potent synaptotoxic oligomers larger may serve neutralize toxic formations. results will add growing debate concerning whether complexes form amyloid plaques are protective through sequestration oligomeric species.