Alzheimer's disease (AD) is currently being addressed by intensive investment in pre-clinical and clinical research on the amyloid hypothesis, but concern remains about the validity of the concept that soluble Aβ oligomers are principally responsible for initiating AD phenotypes. Here, we apply well-defined Aβ oligomers isolated from AD brains or made synthetically to document a systematic accrual of first subtle and then more profound changes in certain synaptic proteins in both primary neuronal cultures and behaving adult mice. Among the first (within hours) synaptic changes are selective decreases in surface levels of certain (e.g., GluA1) but not other (e.g., GluN2B) glutamate receptors and subtle microglial activation. After 4 days, numerous additional synaptic proteins are altered. Moreover, Aβ oligomers induce hyperphosphorylation of tau and subsequent neuritic dystrophy. All changes are prevented by scyllo-inositol in a dose- and stereoisomer-specific manner. Mechanistically, scyllo-inositol interferes quantitatively with the binding of Aβ oligomers to plasma membranes. These comprehensive analyses in culture and in vivo provide direct evidence that diffusible oligomers of human Aβ (without plaques) induce multiple phenotypic changes in healthy neurons, indicating their role as principal endogenous cytotoxins in AD. Our data recommend a re-examination of scyllo-inositol as an anti-oligomer therapeutic in humans with early AD.
Keywords: Alzheimer's disease; Microglia; Scyllo-inositol; Soluble Aβ oligomers; Synapses.
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