Although extensive data support a central pathogenic role for amyloid β protein (Aβ) in Alzheimer's disease1, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Aβ and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell. Cerebral microinjection of cell medium containing these oligomers and abundant Aβ monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Aβ species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Aβ monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Aβ oligomers, in the absence of monomers and amyloid fibrils, disrupted synaptic plasticity in vivo at concentrations found in human brain and cerebrospinal fluid. Finally, treatment of cells with γ-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.
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We thank M. Rosner and V. Chesneau for the gift of the pProExH6HA IDE expression vector, B. Zheng for ELISA analysis, S. Mansourian for assistance in the preparation of illustrations and W. T. Kimberly, W. P. Esler and D. M. Hartley for discussions. Supported by NIH grants (to D.J.S. and M.S.W.) and by Enterprise Ireland and the Health Research Board Ireland (M.R. and R.A.).
The authors declare that they have no competing financial interests
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Walsh, D., Klyubin, I., Fadeeva, J. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002). https://doi.org/10.1038/416535a
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