Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology

Abstract

Alzheimer’s disease (AD), characterized by brain deposits of amyloid-β(Aβ) plaques and neurofibrillary tangles, is also linked to neurovascular dysfunction and blood-brain barrier (BBB) breakdown, affecting the passage of substances into and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in AD. Annexin A1 (ANXA1) is a mediator of glucocorticoids anti-inflammatory action that can suppress microglial activation and reduce BBB leakage. We have reported recently that treatment with recombinant human ANXA1 (hrANXA1) 2reduced Aβ levels by increased degradation in neuroblastoma cells and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient BBB function and decreasing Aβ and tau pathology in 5xFAD mice and Tau-P301L mice. We demonstrate that young 5xFAD mice already suffer cerebrovascular damage, while acute pre-administration of hrANXA1 rescued the vascular defects. Interestingly, the ameliorated BBB permeability in young 5xFAD mice by hrANXA1 correlated with reduced brain A load, due to increased clearance and degradation of Aβ by the insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1 were also observed in 5XFAD mice, increasing IL-10 and reducing TNF-α expression. Additionally, the prolonged treatment with hrANXA1 reduced the memory deficits and increased synaptic density in young 5xFAD mice. Similarly, in Tau-P301L mice, acute hrANXA1 administration restored vascular architecture integrity, affecting the distribution of tight junctions, and reduced tau phosphorylation. The combined data support the hypothesis that the BBB breakdown early in AD can be restored by hrANXA1 as a potential therapeutic approach.