title: Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer's disease: identification of a cellular activation mechanism.
abstract: Receptor-mediated interactions with amyloid beta-peptide (Abeta) could be important in the evolution of the inflammatory processes and cellular dysfunction that are prominent in Alzheimer's disease (AD) pathology. One candidate receptor is the receptor for advanced glycation endproducts (RAGE), which can bind Abeta and transduce signals leading to cellular activation. Data are presented showing a potential mechanism for Abeta activation of microglia that could be mediated by RAGE and macrophage colony-stimulating factor (M-CSF). Using brain tissue from AD and nondemented (ND) individuals, RAGE expression was shown to be present on microglia and neurons of the hippocampus, entorhinal cortex, and superior frontal gyrus. The presence of increased numbers of RAGE-immunoreactive microglia in AD led us to further analyze RAGE-related properties of these cells cultured from AD and ND brains. Direct addition of Abeta(1-42) to the microglia increased their expression of M-CSF. This effect was significantly greater in microglia derived from AD brains compared to those from ND brains. Increased M-CSF secretion was also demonstrated using a cell culture model of plaques whereby microglia were cultured in wells containing focal deposits of immobilized Abeta(1-42). In each case, the Abeta stimulation of M-CSF secretion was significantly blocked by treatment of cultures with anti-RAGE F(ab')2. Treatment of microglia with anti-RAGE F(ab')2 also inhibited the chemotactic response of microglia toward Abeta(1-42). Finally, incubation of microglia with M-CSF and Abeta increased expression of RAGE mRNA. These microglia also expressed M-CSF receptor mRNA. These data suggest a positive feedback loop in which Abeta-RAGE-mediated microglial activation enhances expression of M-CSF and RAGE, possibly initiating an ascending spiral of cellular activation.
authors.affiliation: The Roberts Alzheimer's Disease Center, Sun Health Research Institute, Sun City, Arizona 85372, USA. llue@sunhealth.org
authors.forename: L F
authors.initials: LF
authors.lastname: Lue
authors.forename: D G
authors.initials: DG
authors.lastname: Walker
authors.forename: L
authors.initials: L
authors.lastname: Brachova
authors.forename: T G
authors.initials: TG
authors.lastname: Beach
authors.forename: J
authors.initials: J
authors.lastname: Rogers
authors.forename: A M
authors.initials: AM
authors.lastname: Schmidt
authors.forename: D M
authors.initials: DM
authors.lastname: Stern
authors.forename: S D
authors.initials: SD
authors.lastname: Yan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018728:Entorhinal Cortex / Q000378:metabolism / Q000473:pathology; D005246:Feedback / Q000187:drug effects; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007150:Immunohistochemistry; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D007140:Immunoglobulin Fab Fragments; D010446:Peptide Fragments; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C075222:amyloid beta-protein (1-42); D016173:Macrophage Colony-Stimulating Factor