A study on the molecular mechanisms of neurodegeneration induced by high-mass amyloid-beta assembly, amylospheroids (ASPD)

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Amyloid beta protein (Abeta) plays a central role in Alzheimer's disease (AD). To elucidate the molecular identities of pathogenic Abeta oligomers and their neuronal targets responsible for neurodegeneration, we have previously isolated highly toxic Abeta assemblies termed amylospheroids (ASPD) from AD patient brains. Patient-derived ASPD were toxic to human mature neurons and their amount in AD susceptible regions well correlated with pathological severity of AD. In this study, we found that ASPD neurotoxicity requires Ca2+ influx. We also found that voltage gated calcium channels (VGCC) are involved in ASPD neurotoxicity. Interestingly, the abnormal Ca2+ overload induced by ASPD activated two tau protein kinases, and increased the phosphorylation of tau. Importantly, we found that ASPD-binding to the ASPD target protein on mature neuronal surface impairs its activity, responsible for the above abnormal Ca2+ homeostasis and to the severe neurodegeneration.