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Title: The role of annexin A1 in the regulation of amyloid beta clearance, neuroinflammation, and blood-brain barrier functionality in Alzheimer's disease
Author: Ries, Miriam
ISNI:       0000 0004 8499 3782
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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The main pathological hallmarks of Alzheimer's disease (AD) are amyloid β (Aβ) plaques and neurofibrillary tangles in the brain. Neuroinflammation is strongly implicated in the progression of the disease, supported by the presence of clusters of activated glial cells surrounding Aβ plaques in AD patients and in animal models of AD. An increase in inflammatory mediators released by these glial cells is thought to contribute to the toxicity of Aβ in AD, leading to neuronal dysfunction and cell death. In addition, neurovascular dysfunction and blood-brain barrier (BBB) deficits have been described in AD, potentially as a consequence of both Aβ deposition and neuroinflammation. Annexin A1 (ANXA1) is an anti-inflammatory mediator, which has recently been shown to suppress microglial activation by acting on the formyl peptide receptor 2 (FPR2), and has also been shown to reduce BBB permeability. We hypothesised that ANXA1 has neuroprotective properties in AD, and our aim was to investigate the effects of ANXA1 treatment on Aβ deposition, neuroinflammation, BBB permeability, and memory using in vitro and in vivo models of AD. We show that ANXA1 reduces Aβ load in models of AD by increasing the expression of Aβ degrading enzymes and by stimulating microglial phagocytosis of Aβ. We also show that these effects are mediated by the activation of FPR2. In addition, ANXA1 had anti-inflammatory properties by reversing the Aβ-mediated increase of pro-inflammatory cytokines in vitro and in vivo in the 5xFAD mouse model of amyloidosis. We also found that ANXA1 treatment increases microglial clustering around Aβ plaques and induces the secretion of anti-inflammatory markers, including transforming growth factor β and arginase. These effects were paralleled by increased synaptic density in the hippocampus and reduced memory deficits. Furthermore, we show that administration of ANXA1 is able to reverse BBB leakage and vascular disruption in 5xFAD mice at 12 weeks of age. These data suggest that ANXA1 plays a pivotal role in Aβ clearance, modulating inflammation, and maintaining BBB integrity in AD, and support the further investigation of ANXA1 as a potential pharmacological tool for AD therapeutics.
Supervisor: Sastre, Magdalena ; Solito, Egle ; Piccini, Paola Sponsor: Medical Research Council ; Alzheimer's Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral