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

Abstract

Background Alzheimer's disease (AD) is a neurodegenerative disorder and the predominant type of dementia worldwide. It is characterized by the progressive and irreversible decline of cognitive functions. In addition to the pathological beta-amyloid (Aβ) deposition, glial activation, and neuronal injury in the postmortem brains of AD patients, increasing evidence suggests that the often overlooked vascular dysfunction is an important early event in AD pathophysiology. Vascular endothelial growth factor (VEGF) plays a critical role in regulating physiological functions and pathological changes in blood vessels, but whether VEGF is involved in the early stage of vascular pathology in AD remains unclear. Methods We used an antiangiogenic agent for clinical cancer treatment, the humanized monoclonal anti-VEGF antibody bevacizumab, to block VEGF binding to its receptors in the 5×FAD mouse model at an early age. After treatment, memory performance was evaluated by a novel object recognition test, and cerebral vascular permeability and perfusion were examined by an Evans blue assay and blood flow scanning imaging analysis. Immunofluorescence staining was used to measure glial activation and Aβ deposits. VEGF and its receptors were analyzed by enzyme-linked immunosorbent assay and immunoblotting. RNA sequencing was performed to elucidate bevacizumab-associated transcriptional signatures in the hippocampus of 5×FAD mice. Results Bevacizumab treatment administered from 4 months of age dramatically improved cerebrovascular functions, reduced glial activation, and restored long-term memory in both sexes of 5×FAD mice. Notably, a sex-specific change in different VEGF receptors was identified in the cortex and hippocampus of 5×FAD mice. Soluble VEGFR1 was decreased in female mice, while full-length VEGFR2 was increased in male mice. Bevacizumab treatment reversed the altered expression of receptors to be comparable to the level in the wild-type mice. Gene Set Enrichment Analysis of transcriptomic changes revealed that bevacizumab effectively reversed the changes in the gene sets associated with blood–brain barrier integrity and vascular smooth muscle contraction in 5×FAD mice. Conclusions Our study demonstrated the mechanistic roles of VEGF at the early stage of amyloidopathy and the protective effects of bevacizumab on cerebrovascular function and memory performance in 5×FAD mice. These findings also suggest the therapeutic potential of bevacizumab for the early intervention of AD.

Deletion of Robo4 worsens neuroinflammation and motor coordination in a mouse model of Alzheimer’s disease

“…However, studies of VEGF treatment in mice are inconsistent. One study found that blocking VEGF signaling in AD mice leads to better cognitive function [19], while another study found that VEGF treatment led to better cognitive function in mice [5]. In the context of Robo4, our data and previous studies suggest that the impact of VEGF treatment, whether positive or negative in AD, might depend on the status of Robo/Slit signaling.…”

Normal-Tension Glaucoma and Potential Clinical Links to Alzheimer’s Disease

“…In an AD mouse model, Avastin was able to restore long-term memory, decrease glial activation, and reverse genetic changes associated with blood-brain barrier dysfunction, as seen in AD models [187]. Alternatively, in clinical trials using Avastin in patients with branch retinal vein occlusion with or without NTG, those with NTG had worsened visual acuity even with Avastin treatment.…”

“…Pharmaceutically available VEGF-inhibitors can be delivered as intravitreal injection treatments for neovascular AMD and diabetic macular edema (DME) [178,185]. A specific example of a VEGF-inhibitor that has been used in both treatment of AD and NTG is bevacizumab (Avastin) [186,187].…”