RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction

Kazuhiro Takuma, Fang Fang, Wensheng Zhang, Shiqiang Yan, Emiko Fukuzaki, Heng Du, Alexander Sosunov, Guy McKhann, Yoko Funatsu, Noritaka Nakamichi, Taku Nagai, Hiroyuki Mizoguchi, Daisuke Ibi, Osamu Hori, Satoshi Ogawa, David M. Stern, Kiyofumi Yamada, Shirley Shi Du Yan

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206 Citations (Scopus)

Abstract

Intracellular amyloid-β peptide (Aβ) has been implicated in neuronal death associated with Alzheimer's disease. Although Aβ is predominantly secreted into the extracellular space, mechanisms of Aβ transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of Aβ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Aβ subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of Aβ and protection from Aβ-mediated mitochondrial dysfunction. Aβ activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of Aβ-RAGE complex. Similar intraneuronal co-localization of Aβ and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of Aβ from the extracellular to the intracellular space, thereby enhancing Aβ cytotoxicity.

Original languageEnglish
Pages (from-to)20021-20026
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number47
DOIs
Publication statusPublished - 24-11-2009

All Science Journal Classification (ASJC) codes

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    Takuma, K., Fang, F., Zhang, W., Yan, S., Fukuzaki, E., Du, H., Sosunov, A., McKhann, G., Funatsu, Y., Nakamichi, N., Nagai, T., Mizoguchi, H., Ibi, D., Hori, O., Ogawa, S., Stern, D. M., Yamada, K., & Yan, S. S. D. (2009). RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 106(47), 20021-20026. https://doi.org/10.1073/pnas.0905686106