Amyloid β-protein (Aβ)1-40 protects neurons from damage induced by Aβ1-42 in culture and in rat brain

Kun Zou, Daesung Kim, Atsuko Kakio, Kyunghee Byun, Jian Sheng Gong, Jaewoo Kim, Myeungju Kim, Naoya Sawamura, Sei Ichi Nishimoto, Katsumi Matsuzaki, Bonghee Lee, Katsuhiko Yanagisawa, Makoto Michikawa

研究成果: Article

113 引用 (Scopus)

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Previously, we found that amyloid β-protein (Aβ)1-42 exhibits neurotoxicity, while Aβ1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Aβ1-40 against Aβ1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Aβ1-42 at concentrations higher than 2 μm, which was prevented by concurrent treatment with Aβ1-40 in a dose-dependent manner. However, metal chelators did not prevent Aβ1-42-induced neuronal death. Circular dichroism spectroscopy showed that Aβ1-40 inhibited the β-sheet transformation of Aβ1-42. Thioflavin-T. assay and electron microscopy analysis revealed that Aβ1-40 inhibited the fibril formation of Aβ1-42. In contrast, Aβ1-16, Aβ25-35, and Aβ40-1 did not inhibit the fibril formation of Aβ1-42 nor prevent Aβ1-42-induced neuronal death. Aβ1-42 injection into the rat entorhinal cortex (EC) caused the hyperphosphorylation of tau on both sides of EC and hippocampus and increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the ipsilateral EC, which were prevented by the concurrent injection of Aβ1-40. These results indicate that Aβ1-40 protects neurons from Aβ1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the β-sheet transformation and fibril formation of Aβ1-42. Our data suggest a mechanism by which elevated Aβ1-42/Aβ1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.

元の言語English
ページ(範囲)609-619
ページ数11
ジャーナルJournal of neurochemistry
87
発行部数3
DOI
出版物ステータスPublished - 2003 11 1

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Zou, K., Kim, D., Kakio, A., Byun, K., Gong, J. S., Kim, J., Kim, M., Sawamura, N., Nishimoto, S. I., Matsuzaki, K., Lee, B., Yanagisawa, K., & Michikawa, M. (2003). Amyloid β-protein (Aβ)1-40 protects neurons from damage induced by Aβ1-42 in culture and in rat brain. Journal of neurochemistry, 87(3), 609-619. https://doi.org/10.1046/j.1471-4159.2003.02018.x