VEGF-A in serum protects against memory impairment in APP/PS1 transgenic mice by blocking neutrophil infiltration

Abstract

Activation of innate immunity in the brain is a prominent feature of Alzheimer’s disease (AD). The present study investigated the regulation of innate immunity by wild-type serum injection in a transgenic AD mouse model. We found that treatment with wild-type mouse serum significantly reduced the number of neutrophils and microglial reactivity in the brains of APP/PS1 mice. Mimicking this effect, neutrophil depletion via Ly6G neutralizing antibodies resulted in improvements in AD brain functions. Serum proteomic analysis identified vascular endothelial growth factor-A (VEGF-A) and chemokine (C-X-C motif) ligand 1 (CXCL1) as factors enriched in serum samples, which are crucial for neutrophil migration and chemotaxis, leukocyte migration, and cell chemotaxis. Exogenous VEGF-A reversed amyloid β (Aβ)-induced decreases in cyclin-dependent kinase 5 (Cdk5) and increases in CXCL1 in vitro and blocked neutrophil infiltration into the AD brain. Endothelial Cdk5 overexpression conferred an inhibitory effect on CXCL1 and neutrophil infiltration, thereby restoring memory abilities in APP/PS1 mice. Our findings uncover a previously unknown link between blood-derived VEGF signaling and neutrophil infiltration and support targeting endothelial Cdk5 signaling as a potential therapeutic strategy for AD.

Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer’s disease

“…Strategies such as neuronal overexpression of VEGF, ventricle injection of bone marrow-derived mesenchymal stem cells expressing human VEGF, or direct supplementation of VEGF by brain injection of naked VEGF protein or encapsulated VEGF in biodegradable nanospheres have all been shown to improve memory performance and reduce amyloid plaques in APP/PS1 mice at 6–12 months of age [ 27 , 103 , 104 ]. In addition, intraperitoneal injection of VEGF protein has been shown to reduce neutrophil recruitment into APP/PS1 mice at 8–9 months of age [ 28 ]. These reports suggest the protective effects of ectopically delivered VEGF on the diseased brain of AD.…”

“…Reduced protein levels of ZO-1 have been reported in the brains of Tg2576 AD mice at 11 months of age in both sexes and can be restored by the pan VEGFR and tyrosine kinase inhibitor axitinib [ 105 ]. Reduced protein levels of claudin 5 were also reported in the cortex of male APP/PS1 mice at 8 months of age [ 28 ]. Our results therefore suggest that a decrease in the protein levels of cingulin may be involved in the early onset of hippocampal vascular leakage in female 5×FAD mice before the detectable dysregulation of other BBB-associated proteins, such as ZO-1 and claudin 5, which is a phenomenon that has not been reported previously.…”

“…Peripheral administration of anti-VEGF antibody in 10- to 14-month-old APP/PS1 mice caused both acute and chronic reduction of cortical capillary stalls and vascular permeability, and increase of blood flow [ 11 ]. Although the above study suggests that luminal VEGF may participate in the onset of microvasculature pathology in the middle-aged APP/PS1 mouse model, contradictory findings of neuroprotection by VEGF have also been reported [ 27 , 28 ]. Thus, the impact of VEGF on the disease progression of AD remains uncertain.…”

SARS-CoV-2 vaccination during pregnancy enhances hippocampal neurogenesis and working memory in offspring through IFN-gamma and CX3CR1-dependent mechanisms

“…An LSM 780 confocal laser scanning microscope (Zeiss) was used to capture fluorescence immunostaining images using the same parameters to avoid potential technical artifacts. Imaris 3D surface rendering was used according to the method previously published in our lab 44 . Briefly, IBA1, BrdU, and DCX channels were created separately as a surface after automatic contrast adjustment using Imaris software (Bitplane, version 8.4).…”

SARS-CoV-2 vaccination during pregnancy enhances hippocampal neurogenesis and working memory in offspring via IFN-gamma responsive microglia

“…An LSM 780 confocal laser scanning microscope (Zeiss) was used to capture fluorescence immunostaining images using the same parameters to avoid potential technical artifacts. Imaris 3D surface rendering was used according to the method we previously published 45 . Briefly, IBA1, BrdU, and DCX channels were created separately as a surface after automatic contrast adjustment using Imaris software (Bitplane, version 8.4).…”