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Translational Neurodegeneration
Published in: Translational Neurodegeneration 1/2024

Open Access 01-12-2024 | Bevacizumab | Research

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

Authors: Min Zhang, Zhan Zhang, Honghong Li, Yuting Xia, Mengdan Xing, Chuan Xiao, Wenbao Cai, Lulu Bu, Yi Li, Tae-Eun Park, Yamei Tang, Xiaojing Ye, Wei-Jye Lin

Published in: Translational Neurodegeneration | Issue 1/2024

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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.
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Metadata
Title
Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer’s disease
Authors
Min Zhang
Zhan Zhang
Honghong Li
Yuting Xia
Mengdan Xing
Chuan Xiao
Wenbao Cai
Lulu Bu
Yi Li
Tae-Eun Park
Yamei Tang
Xiaojing Ye
Wei-Jye Lin
Publication date
01-12-2024
Publisher
BioMed Central
Published in
Translational Neurodegeneration / Issue 1/2024
Electronic ISSN: 2047-9158
DOI
https://doi.org/10.1186/s40035-023-00388-4

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