alexa Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior.


Journal of Alzheimers Disease & Parkinsonism

Author(s): Selkoe DJ

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During the last 25 years, neuropathological, biochemical, genetic, cell biological and even therapeutic studies in humans have all supported the hypothesis that the gradual cerebral accumulation of soluble and insoluble assemblies of the amyloid beta-protein (Abeta) in limbic and association cortices triggers a cascade of biochemical and cellular alterations that produce the clinical phenotype of Alzheimer's disease (AD). The reasons for elevated cortical Abeta42 levels in most patients with typical, late-onset AD are unknown, but based on recent work, these could turn out to include augmented neuronal release of Abeta during some kinds of synaptic activity. Elevated levels of soluble Abeta42 monomers enable formation of soluble oligomers that can diffuse into synaptic clefts. We have identified certain APP-expressing cultured cell lines that form low-n oligomers intracellularly and release a portion of them into the medium. We find that these naturally secreted soluble oligomers--at picomolar concentrations--can disrupt hippocampal LTP in slices and in vivo and can also impair the memory of a complex learned behavior in rats. Abeta trimers appear to be more potent in disrupting LTP than are dimers. The cell-derived oligomers also decrease dendritic spine density in organotypic hippocampal slice cultures, and this decrease can be prevented by administration of Abeta antibodies or small-molecule modulators of Abeta aggregation. This therapeutic progress has been accompanied by advances in imaging the Abeta deposits non-invasively in humans. A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging.

This article was published in Behav Brain Res and referenced in Journal of Alzheimers Disease & Parkinsonism

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