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.