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

Miriam Ries,Tsz Wing Chau,Brinda Gurung,Annika Semmler,Robertas Aleksynas,Soha Jamshed Iqbal,James A Pickering,Maria Yanez Lopez,Chris Reutelingsperger,Nicoleta Baxan,Antonio D’Amati,Laura Abelleira-Hervas,Egle Solito,Helena Watts,Magdalena Sastre,Fred Van Leuven,Bibiana Castagna Mota ,Marc Goldfinger ,Steve Gentleman ,Gerard Hernández-Mir ,Carmen Romero‐Molina ,Cornelius K Donat

doi:10.1093/brain/awab050

Abstract

Alzheimer’s disease, characterized by brain deposits of amyloid-β 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-β 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-β 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-β load, due to increased clearance and degradation of amyloid-β by 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 blood–brain barrier breakdown early in Alzheimer’s disease can be restored by hrANXA1 as a potential therapeutic approach.

Highlights

Alzheimer’s disease, the most common form of dementia, is a complex disorder characterized by the progressive decline in memory and cognition, and the accumulation of amyloid-b and tau in the brain, associated with extensive neuroinflammation.[1]
The higher Gd signals in the hippocampus were consistent with blood–brain barrier leakage in young 5xFAD mice and the effect was normalized by treatment with human recombinant ANXA1 (hrANXA1) (Fig. 1C)
The results suggest an increase of D-glucose uptake in young 5xFAD mice compared to wild-type mice and to hrANXA1 treated 5xFAD mice at baseline and at all time points after D-glucose injection (Fig. 1D)

Summary

Introduction

Alzheimer’s disease, the most common form of dementia, is a complex disorder characterized by the progressive decline in memory and cognition, and the accumulation of amyloid-b and tau in the brain, associated with extensive neuroinflammation.[1] Vascular disruption is evident in Alzheimer’s disease brain[2] with blood–brain barrier leakage even at early stages.[3] Damaged blood vessels and blood–brain barrier breakdown were initially associated with amyloid-b and tau pathology in animal models.[4,5] More recently, these alterations were observed in individuals with early cognitive dysfunction regardless of amyloid-b or tau markers.[6] blood–brain barrier disruption is becoming accepted as an early biomarker for Alzheimer’s disease.[7,8,9,10] It remains to be determined whether this is a consequence of neuroinflammation or amyloid-b or tau pathology

Methods

Results

Conclusion