Cited by 295Alzheimer's disease research and treatmentsAdvanced Glycation End Products researchNeuroinflammation and Neurodegeneration Mechanisms

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

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Takuma, Kazuhiro, Fang, Fang, Zhang, Wensheng, Yan, Shiqiang, Fukuzaki, Emiko, Du, Heng, Sosunov, Alexander, McKhann, Guy, Funatsu, Yoko, Nakamichi, Noritaka, Nagai, Taku, Mizoguchi, Hiroyuki, Ibi, Daisuke, Hori, Osamu, Ogawa, Satoshi, Stern, David M., Yamada, Kiyofumi, Yan, Shirley ShiDu·2009·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0905686106PMC PMC2785285

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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.

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Authors: 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.
Affiliations: Kanazawa University (JP)
Columbia University Irving Medical Center (US)
Beijing Normal University (CN)
University of Cincinnati (US)
ORCID: Takuma, Kazuhiro
Zhang, Wensheng
Yan, Shiqiang
Du, Heng
McKhann, Guy
Nakamichi, Noritaka
Nagai, Taku
Mizoguchi, Hiroyuki
Hori, Osamu
Ogawa, Satoshi
Yamada, Kiyofumi
Yan, Shirley ShiDu
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2009-11-24
Volume: 106
Issue: 47
Pages: 20021-20026
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0905686106
PMC: PMC2785285
OpenAlex: W2165298830
Cited by: 290
References: 51
Citations by year: 2026: 8 · 2025: 15 · 2024: 14 · 2023: 13 · 2022: 15 · 2021: 14 · 2020: 10 · 2019: 13 · 2018: 12 · 2017: 20 · 2016: 18 · 2015: 28 · 2014: 21 · 2013: 18 · 2012: 28
FWCI: 15.68
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Lanzhou University Institutional Repository (submittedVersion, cc-by-nc-nd)
Funders: National Institute on Aging (P01AG017490, P01 AG 17490)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: receptor for advanced glycation end products, amyloid-beta, Alzheimer's disease, mitochondrial dysfunction, p38 MAPK, RAGE knockout mice, amyloid precursor protein transgenic mice, neuronal cell death, hippocampus
MeSH terms: Animals, Biological Transport, Brain, Cells, Cultured, Enzyme Activation, Humans, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Neurons, Signal Transduction, Amyloid beta-Peptides, Mice, Knockout, Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, Mice

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

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