Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its effects on synaptic function have not been defined in vivo. Here we report that natural oligomers of human Abeta 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 Abeta monomers but no amyloid fibrils markedly inhibited hippocampal long-term potentiation (LTP) in rats in vivo. Immunodepletion from the medium of all Abeta species completely abrogated this effect. Pretreatment of the medium with insulin-degrading enzyme, which degrades Abeta monomers but not oligomers, did not prevent the inhibition of LTP. Therefore, Abeta 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 gamma-secretase inhibitors prevented oligomer formation at doses that allowed appreciable monomer production, and such medium no longer disrupted LTP, indicating that synaptotoxic Abeta oligomers can be targeted therapeutically.

Alzheimer's disease constitutes a rising threat to public health. Despite extensive research in cellular and animal models, identifying the pathogenic agent present in the human brain and showing that it confers key features of Alzheimer's disease has not been achieved. We extracted soluble amyloid-beta protein (Abeta) oligomers directly from the cerebral cortex of subjects with Alzheimer's disease. The oligomers potently inhibited long-term potentiation (LTP), enhanced long-term depression (LTD) and reduced dendritic spine density in normal rodent hippocampus. Soluble Abeta from Alzheimer's disease brain also disrupted the memory of a learned behavior in normal rats. These various effects were specifically attributable to Abeta dimers. Mechanistically, metabotropic glutamate receptors were required for the LTD enhancement, and N-methyl D-aspartate receptors were required for the spine loss. Co-administering antibodies to the Abeta N-terminus prevented the LTP and LTD deficits, whereas antibodies to the midregion or C-terminus were less effective. Insoluble amyloid plaque cores from Alzheimer's disease cortex did not impair LTP unless they were first solubilized to release Abeta dimers, suggesting that plaque cores are largely inactive but sequester Abeta dimers that are synaptotoxic. We conclude that soluble Abeta oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.

In addition to its role in memory formation, the hippocampus may act as a novelty detector. Here we investigated whether attention to novel events can promote the associative synaptic plasticity mechanisms believed to be necessary for storing those events in memory. We therefore examined whether exposure to a novel spatial environment promoted the induction of activity-dependent persistent increases in glutamatergic transmission (long-term potentiation, LTP) at CA1 synapses in the rat hippocampus. We found that brief exposure to a novel environment lowered the threshold for the induction of LTP. This facilitatory effect was present for a short period following novelty exposure but was absent in animals that explored a familiar environment. Furthermore, the facilitation was dependent on activation of D1/D5 receptors. These findings support an important role for dopamine-regulated synaptic plasticity in the storage of unpredicted information in the CA1 area.

The mechanisms of action of human synthetic and naturally secreted cell-derived amyloid ␤-peptide (A␤) 1-42 on the induction of long-term potentiation (LTP) were investigated in the medial perforant path to dentate granule cell synapses in hippocampal slices.

Despite extensive genetic and animal modelling data that support a central role for the amyloid beta-protein (A beta) in the genesis of Alzheimer's disease, the specific form(s) of A beta which causes injury to neurons in vivo has not been identified. In the present study, we examine the importance of soluble, pre-fibrillar assemblies of A beta as mediators of neurotoxicity. Specifically, we review the role of cell-derived SDS-stable oligomers, their blocking of hippocampal long-term potentiation in vivo and the finding that this blocking can be prevented by prior treatment of oligomer-producing cells with gamma-secretase inhibitors.