Large Soluble Oligomers of Amyloid β-Protein from Alzheimer Brain Are Far Less Neuroactive Than the Smaller Oligomers to Which They Dissociate.

摘要: Soluble oligomers of amyloid β-protein (oAβ) isolated from the brains Alzheimer9s disease (AD) patients have been shown experimentally (in absence plaques) to impair hippocampal synaptic plasticity, decrease synapses, induce tau hyperphosphorylation and neuritic dystrophy, activate microglial inflammation, memory in normal adult rodents. Nevertheless, there has controversy about what types actually confer these AD-like phenotypes. Here, we show that vast majority soluble Aβ species obtained humans who died with confirmed AD elute at high molecular weight (HMW) on nondenaturing size-exclusion chromatography. These little or no cytotoxic activity several bioassays. However, incubation HMW oAβ mildly alkaline buffer led their quantitative dissociation into low (∼8–70 kDa), were now far more bioactive: they impaired LTP, decreased neuronal levels β2-adrenergic receptors, activated microglia wt mice vivo. Thus, most assemblies cortex are large inactive but under certain circumstances can dissociate smaller, highly bioactive species. Insoluble plaques likely sequester oligomers, limiting potential dissociate. We conclude conditions destabilize retard sequestration components important drivers toxicity. Selectively targeting small, forms should be therapeutically beneficial. SIGNIFICANCE STATEMENT Oligomers tought play an role (AD), is confusion sizes disease-relevant activity. Using chromatography three distinct measures bioactivity, predominant aqueous extracts brain relatively inactive. Importantly, conditions, abundant species, significantly synapses than which derived.