AbstractBrain ischaemia is the defining pathological process in vascular dementia (VaD); however, cerebral blood flow is also reduced in Alzheimer’s disease (AD) and there is evidence that hypoperfusion contributes to tissue damage. Vascular endothelial growth factor-A (VEGF) is a pro-angiogenic factor expressed in response to tissue hypoxia. VEGF receptor 2 (VEGFR2) mediates the actions of VEGF on endothelial cells leading to angiogenesis. VEGF receptor 1 (VEGFR1) has limited kinase activity and its soluble form (sVEGFR1) acts as a negative regulator of VEGF. VEGF protein is increased in AD, but without a corresponding increase in microvessel density. Aβ1-42 was shown to bind to VEGFR2 and block signalling in vitro providing a possible mechanism for impaired angiogenesis; however, there are no studies of VEGFR1 or VEGFR2 in AD or VaD.
This thesis investigates whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. Medial parietal cortex and white matter were dissected from AD, VaD and control brains. VEGFR1 and VEGFR2 mRNA and protein levels were measured and related to VEGF and microvessel density. sVEGFR1 isoforms were identified and measured. Human brain microvascular endothelial cells and pericytes were used to investigate VEGFR in response to hypoxia, Aβ1-40 and Aβ1-42.
VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD, though blot analysis on a subset of brains showed an increase in the proportion of sVEGFR1 in AD. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR2 level was similar in AD, VaD and control. The finding that elevated VEGF fails to increase microvessel density in AD despite normal VEGFR2 level raises the possibility that VEGFR2 signalling is defective in AD. The increased proportion of sVEGFR1, supported by in vitro findings, may also contribute to reduced angiogenesis observed in advanced AD.
|Date of Award||25 Jun 2019|
|Supervisor||Seth Love (Supervisor) & Shelley Allen-Birt (Supervisor)|
- Vascular endothelial growth factor
- Alzheimer's disease
- Vascular dementia