抄録
β-Amyloid (Aβ) is a small peptide produced at low levels in normal brain. In the past, aggregation of Aβ into fibrils (senile plaques) was considered to initiate the symptom. However, accumulating evidence supports the toxicity of non-fibrillar oligomers (dimers upto several hudred-mers), which correlates with neuronal dysfunction better than fibrils. Yet, the nature of Aβ oligomers responsible for the pathogenesis remain controversial owing to the heterogeneity of Aβ aggregates in Aβ species and oligomer size. We have previously developed a new method of Aβ aggregation using slow rotation and have found that 10-20-nm Aβspheres was highly toxic to neurons. We termed the newly discovered structure as amylospheroid (ASPD). Other structures including fibrils were nontoxic. Inhibitors experiments suggest that Aβ will form ASPD through a partly distinct pathway from fibrils. Aβ1-42 formed 10-20-nm ASPD by slow rotation. However, Aβ1-42-ASPD is formed more rapidly, killed neurons at lower concentrations, and showed ∼100-fold higher toxicity than Aβ1-40-ASPD. Further studies are in progress to reveal a mechanism underlying neuronal cell death induced by ASPD as well as tracking the ASPD formation to the disease onset in human. In addition, inhibitors, gene therapy, and vaccine therapy are under consideration for development of diagnostics and therapeutic drugs is under consideration through application of these results. Supported by Ministry of Health, Labour and Welfare&MITILS [Jpn J Physiol 55 Suppl:S32 (2005)]
