A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-β oligomeric complexes

The neurotoxicity of amyloid-β protein (Aβ) is widely regarded as one of the fundamental causes of neurodegeneration in Alzheimer's disease (AD). This toxicity is related to Aβ aggregation into oligomers, protofibrils and fibrils. Recent studies suggest that intracellular Aβ, which causes profound toxicity, could be one of the primary therapeutic targets in AD. So far, no compounds targeting intracellular Aβ have been identified. We have investigated the toxicity induced by intracellular Aβ in a neuroblastoma MC65 line and found that it was closely related to intracellular accumulation of oligomeric complexes of Aβ (Aβ-OCs). We further identified a cell-permeable tricyclic pyrone named CP2 that ameliorates this toxicity and significantly reduces the levels of Aβ-OCs. In aqueous solution, CP2 attenuates Aβ oligomerization and prevents the oligomer-induced death of primary cortical neurons. CP2 analogs represent a new class of promising compounds for the amelioration of Aβ toxicities within both intracellular and extracellular sites.