A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid-[beta] oligomeric complexes

• Published in: Journal of neurochemistry 2006-07, Vol.98 (1), p.57
• Main Authors: Maezawa, Izumi, Hyun-Seok, Hong, Wu, Hui-Chuan, Battina, Srinivas K, Rana, Sandeep, Iwamoto, Takeo, Radke, Gary A, Pettersson, Erik, Martin, George M, Hua, Duy H, Lee-Way, Jin
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Apoptosis; Neurons; Proteins; Toxicity
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2006.03862.x

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