Soc for Neurosci Annual Meeting: Explaining Finicky Toxicity of Aβ
9 November 2000. It's a poorly kept secret that Aβ peptides are highly inconsistent in their neurotoxic properties. One batch of synthetic peptide will kill neurons handily, while another will be benign. Sarah Wright and her colleagues at Elan Pharmaceuticals think they may have found an explanation (Abstract 475.12). Using atomic force microscopy and transmission electron microscopy, they examined the structure of Aβ1-40 peptides from different preparations and found that neurotoxicity correlates directly with the composition of aggregate states. All neurotoxic preparations contained a mixture of both fibrils and unaggregated Aβ. Interestingly, adding a small amount (<1%) of fibrillar Aβ to unaggregated peptide will result in a preparation that induces robust cell death (>75%) in primary human and rat cortical neuron cultures. Wright suggests the fibrillar form seeds an ongoing aggregation process, which yields a supply of "protofibrillar" or oligomeric Aβ that is the actual toxic entity, as previously reported by Dean Hartley and William Klein. If others can confirm that mixed preparations are the key to toxicity, one hopes that the debate over Aβ's role can advance to the next level, of determining the toxic mechanism at work and its relevance to Alzheimer's.-June Kinoshita.