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The Journal of Neuroscience, February 2, 2005, 25(5):1071-1080; doi:10.1523/JNEUROSCI.2381-04.2005

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Neurobiology of Disease
Nucleation-Dependent Polymerization Is an Essential Component of Amyloid-Mediated Neuronal Cell Death

Mark Wogulis, Sarah Wright, Damian Cunningham, Tamie Chilcote, Kyle Powell, and Russell E. Rydel

Elan Pharmaceuticals, South San Francisco, California 94080

Accumulating evidence suggests that amyloid protein aggregation is pathogenic in many diseases, including Alzheimer's disease. However, the mechanisms by which protein aggregation mediates cellular dysfunction and overt cell death are unknown. Recent reports have focused on the potential role of amyloid oligomers or protofibrils as a neurotoxic form of amyloid- (A) and related amyloid aggregates. Here we describe studies indicating that overt neuronal cell death mediated by A_1-40 is critically dependent on ongoing A_1-40 polymerization and is not mediated by a single stable species of neurotoxic aggregate. The extent and rate of neuronal cell death can be controlled by conditions that alter the rate of A polymerization. The results presented here indicate that protofibrils and oligomeric forms of A most likely generate neuronal cell death through a nucleation-dependent process rather than acting as direct neurotoxic ligands. These findings bring into question the use of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide formazan assay (MTT assay) as a reporter of A-mediated neuronal cell death and suggest that diffusible A protofibrils and oligomers more likely mediate subtle alterations of synaptic function and long-term potentiation rather than overt neuronal cell death. These results have been extended to A_1-42, the non-A component of Alzheimer's disease amyloid plaques, and human amylin, suggesting that nucleation-dependent polymerization is a common mechanism of amyloid-mediated neuronal cell death. Our findings indicate that ongoing amyloid fibrillogenesis may be an essential mechanistic process underlying the pathogenesis associated with protein aggregation in amyloid disorders.

Key words: Alzheimer's disease; amyloid-; neurotoxicity; neuronal cell death; nucleation-dependent polymerization; amyloidogenic proteins

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Received June 16, 2004; revised December 14, 2004; accepted December 15, 2004.

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