Blockage of VEGF function by bevacizumab alleviates early-stage cerebrovascular dysfunction and improves cognitive function in a mouse model of Alzheimer's disease
查看参考文献128篇
Zhang Min
1,2,3,4
Zhang Zhan
1,4,5,6
Li Honghong
1,5
Xia Yuting
1,7,8
Xing Mengdan
1,4,7,9
Xiao Chuan
1,4,7,9
Cai Wenbao
2,3,4
Bu Lulu
1,5
Li Yi
1,5
Park Tae Eun
10
Tang Yamei
1,4,5,6
*
Ye Xiaojing
2,3,4
*
Lin Wei Jye
1,4,7,9
*
文摘
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 5xFAD 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 ofVEGF 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.
来源
Translational Neurodegeneration
,2024,13(1):1-23 【核心库】
DOI
10.1186/s40035-023-00388-4
关键词
Alzheimer's disease
;
Bevacizumab
;
Vascular endothelial growth factor
;
Cerebrovascular function
地址
1.
Brain Research Center,Sun Yat-sen Memorial Hospital,Sun Yat-sen University, Guangzhou, 510120
2.
Faculty of Forensic Medicine,Zhongshan School of Medicine,Sun Yat-sen University, Guangzhou, 510120
3.
Sun Yat-sen University, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Guangzhou, 510120
4.
Zhongshan School of Medicine,Sun Yat-sen University, Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, 510120
5.
Department of Neurology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University, Guangzhou, 510120
6.
Medical Research Center,Sun Yat-sen Memorial Hos, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation;;Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou, 510120
7.
Medical Research Center,Sun Yat-sen Memorial Hospital,Sun Yat-sen University, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation;;Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Guangzhou, 510120
8.
Sun Yat-sen Memorial Hospital, Nanhai Translational Innovation Center of Precision Immunology, Foshan, 528200
9.
Sun Yat-sen Memorial Hospital, Nanhai Translational Innovation Center of P, Foshan, 528200
10.
Department of Biomedical Engineering,College of Information and Biotechnology,Ulsan National Institute of Science and Technology (UNIST), Republic of Korea, Ulsan, 44919
语种
英文
文献类型
研究性论文
ISSN
2096-6466
学科
神经病学与精神病学
基金
国家自然科学基金
;
Guangzhou Science and Technology Program key projects
;
Guangdong Science and Technology Department
;
the Science and Technology Planning Project of Guangdong Province
;
supported by grants from the Guangdong Project
文献收藏号
CSCD:7756224
参考文献 共
128
共7页
1.
Beam C R. Differences between women and men in incidence rates of dementia and alzheimer's disease.
J Alzheimers Dis,2018,64(4):1077-1083
CSCD被引
1
次
2.
Alzheimer's A. 2016 Alzheimer's disease facts and figures.
Alzheimers Dement,2016,12(4):459-509
CSCD被引
115
次
3.
Tarawneh R. The clinical problem of symptomatic Alzheimer disease and mild cognitive impairment.
Cold Spring Harb Perspect Med,2012,2(5):a006148
CSCD被引
7
次
4.
Uddin M S. Revisiting the role of brain and peripheral Abeta in the pathogenesis of Alzheimer's disease.
J Neurol Sci,2020,416:116974
CSCD被引
3
次
5.
Long J M. Alzheimer disease: an update on pathobiology and treatment strategies.
Cell,2019,179(2):312-339
CSCD被引
112
次
6.
Reitz C. Epidemiology of Alzheimer disease.
Nat Rev Neurol,2011,7(3):137-152
CSCD被引
42
次
7.
Uddin M S. Revisiting the amyloid cascade hypothesis: from anti-abeta therapeutics to auspicious new ways for Alzheimer's disease.
Int J Mol Sci,2020,21(16):5858
CSCD被引
10
次
8.
Uddin M S. Glial cells in Alzheimer's disease: from neuropathological changes to therapeutic implications.
Ageing Res Rev,2022,78:101622
CSCD被引
4
次
9.
Santos C Y. Pathophysiologic relationship between Alzheimer's disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis.
Alzheimers Dement,2017,7:69-87
CSCD被引
2
次
10.
. 2023 Alzheimer's disease facts and figures.
Alzheimers Dement,2023,19(4):1598-1695
CSCD被引
44
次
11.
Ali M. VEGF signalling causes stalls in brain capillaries and reduces cerebral blood flow in Alzheimer's mice.
Brain,2022,145(4):1449-1463
CSCD被引
4
次
12.
Sweeney M D. The role of brain vasculature in neurodegenerative disorders.
Nat Neurosci,2018,21(10):1318-1331
CSCD被引
15
次
13.
Swinford C G. Altered cerebral blood flow in older adults with Alzheimer's disease: a systematic review.
Brain Imaging Behav,2023,17(2):223-256
CSCD被引
1
次
14.
Dai W. Mild cognitive impairment and Alzheimer disease: patterns of altered cerebral blood flow at MR imaging.
Radiology,2009,250(3):856-866
CSCD被引
12
次
15.
Bracko O. Causes and consequences of baseline cerebral blood flow reductions in Alzheimer's disease.
J Cereb Blood Flow Metab,2021,41(7):1501-1516
CSCD被引
2
次
16.
Wiesmann M. Hypertension, cerebrovascular impairment, and cognitive decline in aged AbetaPP/PSl mice.
Theranostics,2017,7(5):1277-1289
CSCD被引
2
次
17.
Heo S. Resting hippocampal blood flow, spatial memory and aging.
Brain Res,2010,1315:119-127
CSCD被引
3
次
18.
Nation D A. Cortical and subcortical cerebrovascular resistance index in mild cognitive impairment and Alzheimer's disease.
J Alzheimers Dis,2013,36(4):689-698
CSCD被引
2
次
19.
Leeuwis A E. Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease.
Alzheimers Dement,2017,13(5):531-540
CSCD被引
4
次
20.
Walker E J. Bevacizumab attenuates VEGF-induced angiogenesis and vascular malformations in the adult mouse brain.
Stroke,2012,43(7):1925-1930
CSCD被引
4
次
了解气象卫星更多信息，请访问