title: Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration.
abstract: OBJECTIVE
  Drusen are hallmarks of age-related macular degeneration (AMD). Amyloid-beta 1-40 (Aβ 1-40), a constituent of drusen, is known to stimulate inflammatory pathways in RPE; however, its effect in vivo is not known. The purpose of this study was to examine the effect of Aβ 1-40 on cytokine expression and inflammasome activation relevant to AMD in an animal model.
  
  
  METHODS
  Wild-type rats received intravitreal injections of Aβ 1-40, and eyes were taken at days 1, 4, 14, and 49 postinjection. The RPE, neuroretina, and vitreous were analyzed for cytokine expression, inflammasome activation, and microglial response via RT-PCR, immunohistochemistry, and suspension array assay. Retinal cell loss was assessed via apoptotic markers and retinal thickness.
  
  
  RESULTS
  Aβ 1-40 stimulated upregulation of IL-6, TNF-α, IL-1β, IL-18, caspase-1, NLRP3, and XAF1 genes in the RPE/choroid and the neuroretina. Increased IL-1β and IL-6 immunoreactivity was found in retinal sections, and elevated levels of IL-1β and IL-18 were found in the vitreous of Aβ-injected eyes. Aβ 1-40 induced a moderate increase in CD11b/c-reactive cells on day 1 postinjection only. No evidence of the proapoptotic XAF1 protein, p53, TUNEL immunoreactivity, or retinal thinning was observed.
  
  
  CONCLUSIONS
  These results confirm earlier in vitro work and support the proinflammatory role of drusen component Aβ 1-40 in the RPE and retina. Inflammasome activation may be responsible for this effect in vivo. This model is useful for understanding cellular triggers of inflammasome activation and proposed early inflammatory events in the outer retina associated with the etiology of AMD.
authors: Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors: Ruozhou Tom
authors: RT
authors: Liu
authors: Jiangyuan
authors: J
authors: Gao
authors: Sijia
authors: S
authors: Cao
authors: Navroop
authors: N
authors: Sandhu
authors: Jing Z
authors: JZ
authors: Cui
authors: Chai Lin
authors: CL
authors: Chou
authors: Edward
authors: E
authors: Fang
authors: Joanne A
authors: JA
authors: Matsubara
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D058847:Inflammasomes / Q000187:drug effects*; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000187:drug effects* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D058847:Inflammasomes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)