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 Alzheimer's disease (AD), the insidious impairment of declarative memory coincides with the accumulation of extracellular amyloid-β protein (Aβ) and intraneuronal tau aggregates. Dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Although numerous studies show that soluble Aβ oligomers inhibit hippocampal long-term potentiation, their role in long-term synaptic depression (LTD) remains unclear. Here, we report that soluble Aβ oligomers from several sources (synthetic, cell culture, human brain extracts) facilitated electrically-evoked LTD in the CA1 region. Aβ-enhanced LTD was mediated by mGluR or NMDAR activity, depending on the induction protocol. Both forms of LTD were prevented by an extracellular glutamate scavenger system. Aβ-facilitated LTD was closely mimicked by the action of the glutamate reuptake inhibitor TBOA, including a shared dependence on extracellular calcium levels and activation of PP2B and GSK-3 signaling. In accord, synaptic glutamate uptake was significantly decreased by soluble Aβ. We conclude that soluble Aβ oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression.

Alzheimer disease is a major cause of cognitive failure, and a pathogenically related but more subtle process accounts for many cases of mild memory symptoms in older humans. Insoluble fibrillar plaques of amyloid β-proteins (Aβ) and neurofibrillary deposits of hyperphosphorylated tau proteins are the diagnostic lesions of AD, but their temporal mechanistic relationship has long been debated. The recent recognition that small, diffusible oligomers may be the principal bioactive form of Aβ raises the key question of whether these are sufficient to initiate cytoskeletal change and neurite degeneration. A few studies have examined the effects of oligomers of synthetic Aβ peptides of one defined length at supraphysiological concentrations, but the existence of such assemblies in the AD brain is not established. Here, we isolated Aβ dimers, the most abundant form of soluble oligomer detectable in the human brain, from the cortices of typical AD subjects and found that at subnanomolar concentrations, they first induced hyperphosphorylation of tau at AD-relevant epitopes in hippocampal neurons and then disrupted the microtubule cytoskeleton and caused neuritic degeneration, all in the absence of amyloid fibrils. Application of pure, synthetic dimers confirmed the effects of the natural AD dimers, although the former were far less potent. Knocking down endogenous tau fully prevented the neuritic changes, whereas overexpressing human tau accelerated them. Coadministering Aβ N-terminal antibodies neutralized the cytoskeletal disruption. We conclude that natural dimers isolated from the AD brain are sufficient to potently induce AD-type tau phosphorylation and then neuritic dystrophy, but passive immunotherapy mitigates this.A lzheimer disease (AD) and its harbinger, mild cognitive impairment-amnestic type, comprise the most prevalent latelife cognitive disorder in humans. The aging of the population in developed nations has led to predictions that the prevalence of Alzheimer-type dementia will rise substantially during the next few decades. Intensive research over almost 30 y has led to the hypothesis that progressive cerebral accumulation of the 42-residue amyloid β-protein (Aβ) may precipitate the synaptic dysfunction and cytoskeletal changes that underlie the symptoms of AD (1). Although insoluble amyloid plaques are one of the two neuropathological hallmarks of AD, recent studies suggest that these are in equilibrium with small, diffusible oligomers of Aβ that may serve as the principal synaptotoxic form of the protein (2).A major unresolved question about AD pathogenesis is the relationship of Aβ deposits to the other cardinal lesion of the disease, the neurofibrillary tangle. These two lesions occur together in virtually all cases of AD, but whether Aβ build-up is directly responsible for the neurofibrillary degeneration of AD is the subject of debate. Specifically, the growing experimental evidence that key features of the AD phenotype, such as dendritic spine loss, altered hippocampal synaptic plasticity, and impa...