Spherical aggregates of β-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3β

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Abstract
β-Amyloid (Aβ) acquires toxicity by self-aggregation. To identify and characterize the toxic form(s) of Aβ aggregates, we examined in vitro aggregation conditions by using large quantities of homogenous, chemically synthesized Aβ1–40 peptide. We found that slow rotation of Aβ1–40 solution reproducibly gave self-aggregated Aβ1–40 containing a stable and highly toxic moiety. Examination of the aggregates purified by glycerol-gradient centrifugation by atomic force microscopy and transmission electron microscopy revealed that the toxic moiety is a perfect sphere, which we call amylospheroid (ASPD). Other Aβ1–40 aggregates, including fibrils, were nontoxic. Correlation studies between toxicity and sphere size indicate that 10- to 15-nm ASPD was highly toxic, whereas ASPD 10 nm also appeared to exist when Aβ1–42 formed ASPD by slow rotation. However, Aβ1–42-ASPD formed more rapidly, killed neurons at lower concentrations, and showed ≈100-fold-higher toxicity than Aβ1–40-ASPD. The toxic ASPD was associated with SDS-resistant oligomeric bands in immunoblotting, which were absent in nontoxic ASPD. Because the formation of ASPD was not disturbed by pentapeptides that break β-sheet interactions, Aβ may form ASPD through a pathway that is at least partly distinct from that of fibril formation. Inhibition experiments with lithium suggest the involvement of tau protein kinase I/glycogen synthase kinase-3β in the early stages of ASPD-induced neurodegeneration. Here we describe the identification and characterization of ASPD and discuss its possible role in the neurodegeneration in Alzheimer9s disease.