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Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and improves cortical blood flow in an Alzheimer’s disease mouse model
Author(s) -
Ali Muhammad,
Falkenhain Kaja,
HaftJavaherian Mohammad,
MurtazaAli Muhammad,
Njiru Brendah N,
Nishimura Nozomi,
Schaffer Chris B,
Bracko Oliver
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.047622
Subject(s) - occludin , blood–brain barrier , vascular permeability , tight junction , vascular endothelial growth factor , cerebral blood flow , chemistry , pathology , blood flow , medicine , biology , endocrinology , microbiology and biotechnology , vegf receptors , central nervous system
Abstract Background We recently found that increased obstructions in capillaries caused by adhesion of leucocytes in the cortical microvascular leads to a ∼20% reduction of cerebral blood flow (CBF) in mouse models of Alzheimer’s disease. Here, we explore the contribution of peripheral Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature as a driver of capillary stalling and blood‐brain barrier (BBB) integrity in the APP/PS1 mouse model of AD. Method The number of stalled cortical capillaries and blood flow speeds were measured in cortical capillaries using high resolution in vivo two‐photon imaging, before and after one hour and two weeks of i.p. anti‐VEGF164 antibody injection. Capillary stalls were measured using the citizen science platform Stall Catchers. The blood‐brain barrier integrity was analyzed using immunohistochemistry. Result We found that inhibition of VEGF signaling in APP/PS1 mice reduces capillary stalling by ∼75% and improves average capillary speed by ∼50%. In contrast, no such effects were seen in wild‐type saline‐injected controls. The anti‐VEGF164 injection also reduced overall eNOS protein concentrations and increased the tight junction protein levels of occludin. Intriguingly, the few APP/PS1 capillaries that were still prone to obstructions after anti‐VEGF treatment had lower occludin concentrations between their endothelial cells than flowing capillaries. We further demonstrate that capillary stalling reductions and capillary speed improvements occur within an hour of intraperitoneal anti‐mouseVEGF164 injection. At the same time scale, anti‐VEGF treatment reduced Evan’s blue diffusion across the BBB. Conclusion This data demonstrates that peripheral inhibition of VEGF‐signaling in APP/PS1 mice restores aberrant eNOS/occludin‐associated BBB permeability, and is associated with decreased capillary stalls and increased CBF.