Increased intrathecal levels of the angiogenic factors VEGF and TGF-β in Alzheimer’s disease and vascular dementia

Tarkowski, E; Issa, Razao; Sjögren, Magnus; Wallin, Anders; Blennow, Kaj; Tarkowski, Andrej; Kumar, Patricia

doi:10.1016/s0197-4580(01)00285-8

Cited by 331 publications

(241 citation statements)

References 33 publications

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“…decreased cholinergic innervation of intracerebral bloodvessels [10,11], reduced NO production [12][13][14][15] and an increase in vasoconstrictors EDN1 [16,19] and AngII, through upregulation of angiotensin-converting enzyme (ACE)-1 and downregulation of ACE-2 [17,18]) may all contribute to reduced cerebral blood flow (CBF). Reduced tissue oxygenation leads to increased VEGF [3,[29][30][31][32] that is not accompanied by an increase in endothelial von Willebrand factor (vWF) level and microvessel density [3]. Reduction in VEGFR1 is probably a physiological response to reduced oxygenation but an increase in the soluble …”

Section: Discussionmentioning

confidence: 99%

“…It is upregulated in response to hypoxia [27,28] and elevated within hypoperfused cortex and white matter in small vessel disease, vascular dementia and AD [3,[29][30][31][32]. Its effects are mediated by the tyrosine kinase receptors, vascular endothelial growth factor receptors 1 and 2 (VEGFR1 and VEGFR2), neuropilin (NRP1 and NRP2) and heparan sulfate proteoglycans (HSPGs) co-receptors.…”

Section: Introductionmentioning

confidence: 99%

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VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-␤, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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“…In the CNS, however, cytokines are secreted by microglia and astrocytes and have been linked to CNS development. Moreover, enhanced expression of proinflammatory cytokines, such as IL-6, IL-10, IL-1b, TNF-a, are observed in the brain and cerebrospinal fluid (CSF) of Alzheimer's patients (Blum-Degen et al 1995;Jiang et al 2011;Mrak and Griffin 2005;Tarkowski et al 2002). In the animal models of AD, the expression level of TNF-a, IL-1a and IL-1b was also reported to be elevated (Apelt and Schliebs 2001;Benzing et al 1999;Matsuoka et al 2001;Sly et al 2001).…”

Section: Inflammatory Cytokines and Chemokinesmentioning

confidence: 99%

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Zhang

et al. 2015

Arch. Immunol. Ther. Exp.

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Alzheimer's disease (AD) is a complex agerelated neurodegenerative disorder of the central nervous system. Since the first description of AD in 1907, many hypotheses have been established to explain its causes. The inflammation theory is one of them. Pathological and biochemical studies of brains from AD individuals have provided solid evidence of the activation of inflammatory pathways. Furthermore, people with long-term medication of anti-inflammatory drugs have shown a reduced risk to develop the disease. After three decades of genetic study in AD, dozens of loci harboring genetic variants influencing inflammatory pathways in AD patients has been identified through genome-wide association studies (GWAS). The most well-known GWAS risk factor that is responsible for immune response and inflammation in AD development should be APOE e4 allele. However, a growing number of other GWAS risk AD candidate genes in inflammation have recently been discovered. In the present study, we try to review the inflammation in AD and immunity-associated GWAS risk genes like HLA-DRB5/DRB1, INPP5D, MEF2C, CR1, CLU and TREM2.

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“…Using adenoviral vector delivery VEGF (AdhVEGF) in the mouse brain, we have successfully developed a focal brain angiogenesis model (Xu et al, 2003). Clinical studies demonstrate that VEGF is greatly increased in hemorrhagic stroke, cerebral ischemia, Alzheimer disease, and human BAVM (Hayashi et al, 2003;Sonstein et al, 1996;Tarkowski et al, 2002;Zhang et al, 2000). However, the nature of VEGF-induced angiogenesis in the normal adult brain is unknown.…”

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confidence: 99%

Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

Huey

et al. 2004

J Cereb Blood Flow Metab

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Summary:Hereditary hemorrhagic telangiectasia (HHT), associated with brain arteriovenous malformations, is caused by a loss of function mutation in either the endoglin (HHT1) or activin receptor-like kinase 1 gene (ALK-1, HHT2). Endoglin heterozygous (Eng +/− )mice have been proposed as a disease model. To better understand the role of endoglin in vascular malformation development, we examined the effect of vascular endothelial growth factor (VEGF) hyperstimulation on microvessels in adult endoglin heterozygous (Eng +/− ) mice using an adenoviral vector to deliver recombinant human VEGF 165 cDNA (AdhVEGF) into basal ganglia. VEGF expression was increased in AdhVEGF mice compared with the AdlacZ and saline group (P < 0.05) and localized to multiple cell types (neurons, astrocytes, endothelial cells, and smooth muscle cells) by double-labeled immunostaining. VEGF overexpression increased microvessel count for up to 4 weeks in both the Eng +/+ and Eng +/− groups (Eng +/+ 185 ± 14 vs. Eng +/− 201 ± 10 microvessels/mm 2 ). Confocal microscopic examination revealed grossly abnormal microvessels in eight of nine Eng +/− mouse brains compared with zero of nine in Eng +/+ mice (P < 0.05). Abnormal microvessels featured enlargement, clustering, twist, or spirals. VEGF receptor Flk-1 and TGF-␤ receptor 1 (T␤R1) expression were reduced in the Eng +/− mouse brain compared with control.Excessive VEGF stimulation may play a pivotal role in the initiation and development of brain vessel malformations in states of relative endoglin insufficiency in adulthood. These observations are relevant to our general understanding of the maintenance of vascular integrity.

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Increased intrathecal levels of the angiogenic factors VEGF and TGF-β in Alzheimer’s disease and vascular dementia

Cited by 331 publications

References 33 publications

VEGFR1 and VEGFR2 in Alzheimer’s Disease

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Inflammation in Alzheimer’s Disease and Molecular Genetics: Recent Update

Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

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