Abstract
BackgroundThe 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.MethodsWe 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.ResultsOur 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.ConclusionsThese data suggest that ANXA1 plays a pivotal role in Aβ clearance and supports the use of ANXA1 as potential pharmacological tool for AD therapeutics.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0692-6) contains supplementary material, which is available to authorized users.
Highlights
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
Annexin A1 (ANXA1) is increased in postmortem brains of AD patients and in 5XFAD mice ANXA1 expression was determined in homogenates of human postmortem frontal cortex from AD patients and in age-matched healthy control brains
Supporting data obtained in human AD cases, a 50 % increase in ANXA1 expression was observed in brain homogenates of 5XFAD mice at 12 weeks of age (n = 6/group, Fig. 1b)
Summary
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. There is convincing evidence that Aβ is able to prime microglia [3], inciting an inflammatory response and the release of neurotoxic cytokines, ROS, complement factors and nitric oxide (NO), which can all contribute to neuronal dysfunction and cell death [4]. Activated microglia can reduce Aβ accumulation by increasing its phagocytosis, clearance and degradation [8, 9] and the release of anti-inflammatory molecules including certain cytokines, growth factors and the resolving molecule Annexin A1 (ANXA1)
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