Annexin-A1 restores cerebrovascular integrity concomitant with reduced amyloid-β and tau pathology
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Submitted version
Embargoed until: 7777-01-01
Reason: Unidentified version
Embargoed until: 7777-01-01
Reason: Unidentified version
Volume
144
Pagination
1526–1541
Publisher
Publisher URL
DOI
10.1093/brain/awab050
Journal
Brain
Issue
Metadata
Show full item recordAbstract
Alzheimer’s disease, characterized by brain deposits of amyloid-b plaques and neurofibrillary tangles, is also
linked to neurovascular dysfunction and blood–brain barrier breakdown, affecting the passage of substances into
and out of the brain. We hypothesized that treatment of neurovascular alterations could be beneficial in
Alzheimer’s disease. Annexin A1 (ANXA1) is a mediator of glucocorticoid anti-inflammatory action that can suppress microglial activation and reduce blood–brain barrier leakage. We have reported recently that treatment with
recombinant human ANXA1 (hrANXA1) reduced amyloid-b levels by increased degradation in neuroblastoma cells
and phagocytosis by microglia. Here, we show the beneficial effects of hrANXA1 in vivo by restoring efficient
blood–brain barrier function and decreasing amyloid-b 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 blood–brain barrier permeability in young
5xFAD mice by hrANXA1 correlated with reduced brain amyloid-b load, due to increased clearance and degradation of amyloid-b by insulin degrading enzyme (IDE). The systemic anti-inflammatory properties of hrANXA1
were also observed in 5xFAD mice, increasing IL-10 and reducing TNF-a 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
blood–brain barrier breakdown early in Alzheimer’s disease can be restored by hrANXA1 as a potential therapeutic
approach.