Elucidation of the neurodegenerative mechanism induced by amylospheroid

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Oligomerization of β-amyloid (Aβ) has been hypothesized to initiate the pathogenic cascade of Alzheimer's disease (AD). Recent studies have shown that instead of fibrils, soluble oligomers are regarded as the substance of neurotoxicity, yet the physical and biochemical features of the toxic oligomers are still unclear. Among various Aβ oligomers including fibrils, we have previously identified and purified 10-15-nm spheres as the most toxic species in vitro, which we call amylospheroid (ASPD) (Hoshi et al. PNAS 2003). Recently we obtained the data suggesting the in vivo presence of ASPD (Noguchi, A., Matsumura, S., Hoshi, M., manuscript in preparation). These results raise the possibility that ASPD or ASPD-like molecule plays a potential role in the AD process. Therefore, elucidation of the ASPD formation will contribute to clarify which environments and how they induce the formation of the toxic Aβ oligomers in AD brains as well as to AD therapeutics.In this study, we have examined the chemical environments that promote ASPD formation and reasoned that ASPD formation is off the pathway to fibrils. It should be noted that in every conditions examined, neurotoxicity correlated solely with the formation of 10-15-nm ASPD. Furthermore, we addressed the question whether Aβ with familial mutations in its sequence, D7N-Aβ (Tottori) or E22G-Aβ (Arctic), forms ASPD as observed in the case of wild type Aβ. The neurotoxicity as well as the formation efficiency of ASPD derived from these mutants will also be presented (Noguchi, A., Hoshi, M., unpublished data). We also found that ASPD induced calcium influx in neurons which lead to calpain activation and co1comitant cell death (Kikuchi, S., Yanazawa, M., Hoshi, M., manuscript in preparation).