Inhibitors of Amyloid beta aggregation prevent and reverse Alzheimer

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When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid peptide (A) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease–like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral A pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease–like phenotype, support the idea that the accumulation of A oligomers has a central role in the pathogenesis of Alzheimer disease.
Multiple lines of evidence suggest that the accumulation of neurotoxic oligomeric aggregates of A may be a central event in the pathogenesis of Alzheimer disease1, 2. If correct, this hypothesis predicts that inhibitors of A aggregation and toxicity may be effective in blocking this pathogenic cascade. We report here that orally administered cyclohexanehexol stereoisomers can block the accumulation of A oligomers in a dose-dependent manner, and reduce Alzheimer disease–like behavioral deficits, Alzheimer disease–like neuropathology and accelerated mortality in a transgenic mouse model of Alzheimer disease. These in vivo experimental results both strongly support the notion that accumulation of A oligomers has a significant role in the pathogenesis of Alzheimer disease and suggest that inhibition of A aggregation may be a useful therapy for this disease.