title: IVIG immunotherapy protects against synaptic dysfunction in Alzheimer's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway.
abstract: BACKGROUND
  Complement component C5-derived C5a locally generated in the brain has been shown to protect against glutamate-induced neuronal apoptosis and beta-amyloid (Aβ) toxicity, but the mechanism is not clear. In this study, we tested the hypothesis that C5a influences upstream signal transduction pathways associated with cAMP-response element-binding protein (CREB) activation, in which alterations of CREB levels are associated with cognitive deterioration in AD.
  
  
  METHODS
  CREB signaling pathway, synaptic plasticity and cognitive function were studied in C5a receptor knockout mice (C5aR(-/-)), C5a over expressing mice (C5a/GFAP) and in Tg2576 mice, an AD mouse model.
  
  
  RESULTS
  (1) Cognitive function is severely impaired in C5aR(-/-) mice, coincident with the down-regulated CREB/CEBP pathway in brain. (2) Either the application of recombinant-human-C5a (hrC5a) or exogenous expression of C5a in the brain of a mouse model (C5a/GFAP) enhances this pathway. (3) Application of hrC5a in brain slices from Tg2576 mice significantly improves deficits in long-term potentiation (LTP), while this effect is blocked by a specific AMPA receptor antagonist. (4) Searching for a pharmacological approach to locally mediate C5a responses in the brain, we found that low-dose human intravenous immunoglobulin (IVIG) treatment improves synaptic plasticity and cognitive function through C5a-mediated induction of the CREB/CEBP pathway, while the levels of Aβ in the brain are not significantly affected.
  
  
  CONCLUSIONS
  This study for the first time provides novel evidence suggesting that C5a may beneficially influence cognitive function in AD through an up-regulation of AMPA-CREB signaling pathway. IVIG may systematically improve cognitive function in AD brain by passing Aβ toxicity.
authors.affiliation: Department of Neurology, Center of Excellence for Novel Approaches to Neurotherapeutics, Mount Sinai School of Medicine, New York, NY 10029, United States.
authors.forename: Bing
authors.initials: B
authors.lastname: Gong
authors.forename: Yong
authors.initials: Y
authors.lastname: Pan
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Lindsay
authors.initials: L
authors.lastname: Knable
authors.forename: Prashant
authors.initials: P
authors.lastname: Vempati
authors.forename: Shimul
authors.initials: S
authors.lastname: Begum
authors.forename: Lap
authors.initials: L
authors.lastname: Ho
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Shrishailam
authors.initials: S
authors.lastname: Yemul
authors.forename: Scott
authors.initials: S
authors.lastname: Barnum
authors.forename: Amanda
authors.initials: A
authors.lastname: Bilski
authors.forename: Ben Y
authors.initials: BY
authors.lastname: Gong
authors.forename: Giulio M
authors.initials: GM
authors.lastname: Pasinetti
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D015936:Complement C5a / Q000235:genetics / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018091:Receptors, AMPA / Q000819:agonists / Q000378:metabolism*; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055366:Synaptic Potentials / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism / Q000494:pharmacology
chemical_list: D016564:Amyloid beta-Protein Precursor; D022762:CCAAT-Enhancer-Binding Proteins; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D016756:Immunoglobulins, Intravenous; D018091:Receptors, AMPA; D011951:Receptors, Complement; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D015936:Complement C5a
keywords: Alzheimer's disease; Cognitive function; Complement component C5a; IVIG; LTP; pCREB