title: The anti-inflammatory Annexin A1 induces the clearance and degradation of the amyloid-β peptide.
abstract: The toxicity of amyloid-β (Aβ) peptide present in the brain of Alzheimer's disease (AD) patients is thought to be mediated via the increased secretion of pro-inflammatory mediators, which can lead to neuronal dysfunction and cell death. In addition, we have previously shown that inflammation can affect Aβ generation. More recently, we have reported that in vitro administration of the anti-inflammatory mediator Annexin A1 (ANXA1) following an inflammatory challenge suppressed microglial activation and this effect was mediated through formyl peptide receptor-like 1 (FPRL1/FPR2) signalling. The aim of this study was to determine the potential role of ANXA1 in the generation and clearance of Aβ.
  
  
  
  We first compared ANXA1 protein expression in the brains of AD patients and healthy controls as well as in the 5XFAD model of AD. To determine the role of ANXA1 in the processing of amyloid precursor protein (APP) and the degradation of Aβ, N2a neuroblastoma cells were treated with human recombinant ANXA1 or transfected with ANXA1 siRNA. We also investigated the effect of ANXA1 on Aβ phagocytosis and microglial activation in BV2 cells treated with synthetic Aβ.
  
  
  
  Our data show that ANXA1 is increased in the brains of AD patients and animal models of AD at early stages. ANXA1 was able to reduce the levels of Aβ by increasing its enzymatic degradation by neprilysin in N2a cells and to stimulate Aβ phagocytosis by microglia. These effects were mediated through FPRL1 receptors. In addition, ANXA1 inhibited the Aβ-stimulated secretion of inflammatory mediators by microglia.
  
  
  
  These data suggest that ANXA1 plays a pivotal role in Aβ clearance and supports the use of ANXA1 as potential pharmacological tool for AD therapeutics.
authors: Division of Brain Sciences, Hammersmith Hospital, Imperial College London, London, W12 0NN, UK.
authors: Miriam
authors: M
authors: Ries
authors: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
authors: Rodrigo
authors: R
authors: Loiola
authors: Division of Brain Sciences, Hammersmith Hospital, Imperial College London, London, W12 0NN, UK.
authors: Urvi N
authors: UN
authors: Shah
authors: Division of Brain Sciences, Hammersmith Hospital, Imperial College London, London, W12 0NN, UK.
authors: Steve M
authors: SM
authors: Gentleman
authors: William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK. e.solito@qmul.ac.uk.
authors: Egle
authors: E
authors: Solito
authors: Division of Brain Sciences, Hammersmith Hospital, Imperial College London, London, W12 0NN, UK. m.sastre@imperial.ac.uk.
authors: Magdalena
authors: M
authors: Sastre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017305:Annexin A1 / Q000378:metabolism / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017305:Annexin A1; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C509690:tryptophyl-arginyl-tryptophyl-tryptophyl-tryptophyl-tryptophanamide
keywords: Alzheimer’s disease; Amyloid-β; Annexin A1; Anti-inflammatory; Formyl-peptide receptor; Inflammation; Microglia; Neprilysin