RAGE-mediated signaling contributes to intraneuronal transport of amyloid-β and neuronal dysfunction
Open accessAbstract
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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ApoE facilitates but is not required for Aβ uptake, because neurons grown in the absence of ApoE can internalize Aβ.
“As shown by us and others, ApoE facilitates but it is not required for Ab uptake, because neurons grown in the absence of ApoE can internalize Ab. 28”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [28]
Evidence suggests that internalization of Aβ not associated with ApoE occurs through nonendocytotic mechanisms, based on translocation of cell surface bound Aβ directly to the cytosol, and results in accumulation of Aβ primarily outside the endosomal/lysosomal compartment.
“In contrast, evidence suggests that internalization of Ab not associated with ApoE occurs through nonendocytotic mechanisms, which are based on the translocation of the cell surface bound Ab directly to the cytosol and results in accumulation of Ab primarily outside the endosomal/lysosomal compartment.28,45,46”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [28]
RAGE is not known to be related to oxytocin or oxytocin signalling.
“RAGE, a member of the immunoglobulin superfamily of pattern recognition receptors, is not known to be related to oxytocin or oxytocin signalling22–33.”
From Vascular RAGE transports oxytocin into the brain to elicit its maternal bonding behaviour in mice (2019) · cites this paper as [25]
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“Consistent with these in vitro results, recent studies in brains of AD patients (48) and another mouse AD model (49) displayed striking accumulation of A in hippocampal pyramidal cells.”
ResultRAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease
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“RAGE is a receptor of the immunoglobulin super family that is found in BBB and that is responsible for the Aβ transport, from the blood to the brain, leading to mitochondrial dysfunction (Takuma et al., 2009).”
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RAGE Expression and ROS Generation in Neurons: Differentiation versus Damage
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“Synaptotoxicity appears to concern both extracellular and intracellular Ab.”
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Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses
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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
- 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
- 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
- Health Sciences › Medicine › Physiology › 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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