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Abstract

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-β, 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.

Original languageEnglish
Pages (from-to)741-752
Number of pages12
JournalJournal of Alzheimer's Disease
Volume61
Issue number2
Early online date19 Dec 2017
DOIs
Publication statusPublished - 2018

Keywords

  • Alzheimer’s disease
  • brain ischemia
  • microvessels
  • vascular endothelial growth factor A
  • vascular endothelial growth factor receptor-1
  • vascular endothelial growth factor receptor-2

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  • Student Theses

    VEGFR1 and VEGFR2 in dementia

    Author: Harris, R. E., 25 Jun 2019

    Supervisor: Love, S. (Supervisor) & Allen-Birt, S. (Supervisor)

    Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

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