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

• Minako Hoshi

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

• Michio Sato

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

• Shinichiro Matsumoto

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

• Akihiko Noguchi

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

• Kaori Yasutake

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

• Natsuko Yoshida

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

• Kazuki Sato

  Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan; PRESTO, Japan Science and Technology Corp., and CACs, Inc., 1000 Kamoshida, Aobaku, Yokohama 227-0033, Japan

抄録

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 Aβ 1–40 peptide. We found that slow rotation of Aβ 1–40 solution reproducibly gave self-aggregated Aβ 1–40 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 Aβ 1–40 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 was nontoxic. A positive correlation between the toxicity and ASPD >10 nm also appeared to exist when Aβ 1–42 formed ASPD by slow rotation. However, Aβ 1–42 -ASPD formed more rapidly, killed neurons at lower concentrations, and showed ≈100-fold-higher toxicity than Aβ 1–40 -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 Alzheimer's disease.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 100 (11), 6370-6375, 2003-05-15

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1360011146184576896
• NII論文ID: 80016013987
• DOI: 10.1073/pnas.1237107100
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.1237107100
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