title: RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction.
abstract: Intracellular amyloid-beta peptide (Abeta) has been implicated in neuronal death associated with Alzheimer's disease. Although Abeta is predominantly secreted into the extracellular space, mechanisms of Abeta 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 Abeta from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human Abeta 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 Abeta and protection from Abeta-mediated mitochondrial dysfunction. Abeta activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of Abeta-RAGE complex. Similar intraneuronal co-localization of Abeta 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 Abeta from the extracellular to the intracellular space, thereby enhancing Abeta cytotoxicity.
authors.affiliation: Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takuma
authors.forename: Fang
authors.initials: F
authors.lastname: Fang
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
authors.forename: Shiqiang
authors.initials: S
authors.lastname: Yan
authors.forename: Emiko
authors.initials: E
authors.lastname: Fukuzaki
authors.forename: Heng
authors.initials: H
authors.lastname: Du
authors.forename: Alexander
authors.initials: A
authors.lastname: Sosunov
authors.forename: Guy
authors.initials: G
authors.lastname: McKhann
authors.forename: Yoko
authors.initials: Y
authors.lastname: Funatsu
authors.forename: Noritaka
authors.initials: N
authors.lastname: Nakamichi
authors.forename: Taku
authors.initials: T
authors.lastname: Nagai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ibi
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: David M
authors.initials: DM
authors.lastname: Stern
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Shirley Shidu
authors.initials: SS
authors.lastname: Yan
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases