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Induction of fibril-like beta-amyloid aggregates by a natural substance decreases soluble oligomers and protects from neurotoxicity
Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease belong to the group of brain amyloid disorders and involve the formation and accumulation of misfolded disease-specific proteins. According to the amyloid cascade hypothesis, accumulation of the amyloid-beta peptide(A-beta) is central for the pathogenesis of Alzheimer's disease. Increasing evidence suggests that soluble precursor aggregates such as oligomers rather than insoluble amyloid fibrils are responsible for synaptic dysfunction, axonal and dendritic degeneration, and neuronal death. Reducing the prevalence of the toxic aggregate species represents a potential therapeutic strategy. In this study, we have identified a natural substance as a potent modulator of A-beta aggregation. It significantly reduced the amount of soluble oligomers and accelerated the formation of large insoluble aggregates with a fibril-like morphology. The neurotoxicity of A-beta aggregates generated in the presence of the natural substance was reduced. In addition, the modulator prevented the A-beta-mediated impairment of hippocampal long-term potentiation, an electrophysiological correlate of memory function, in rat brain slices. Hence, diminishing soluble toxic A-beta aggregates by small molecules likely preserves synaptic function and may be neuroprotective in Alzheimer's Disease.