Journal
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
Volume 36, Issue 6, Pages 487-497Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1365-2990.2010.01084.x
Keywords
Alzheimer's disease; beta-amyloid; cerebral blood flow; cerebrovascular dysfunction; endothelin; endothelin-converting enzyme
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Funding
- BRACE (Bristol Research into Alzheimer's and Care of the Elderly)
- Alzheimer's Research Trust
- Alzheimers Research UK [ART-EG2005B-1, ART-EG2003A-3] Funding Source: researchfish
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Aims: Alzheimer's disease (AD) is believed to be caused by the accumulation of amyloid beta (A beta) peptide within the brain. Endothelin-converting enzyme-1 and 2 (ECE-1 and ECE-2) are expressed in endothelial cells and neurones, respectively, and both cleave 'big endothelin' to produce the vasoconstrictor endothelin-1 (ET-1). ECE-1 and ECE-2 also degrade A beta. AD patients have regionally reduced microvascular blood flow in the brain, with impaired endothelium-dependent relaxation and cerebrovascular autoregulation, and abnormal production of ET-1 has been demonstrated in mice overexpressing amyloid precursor protein. We recently found ECE-2 mRNA and protein to be elevated in the brain in AD. In vitro, expression of ECE-2 was upregulated by A beta. Our aims for this study were to examine expression of ECE-1 (which has 57% homology with ECE-2) in temporal cortex from patients with AD, vascular dementia (VaD) and controls. Methods: We examined the distribution of ECE-1 with immunohistochemistry, and measured ECE-1 mRNA by real-time polymerase chain reaction (PCR). ECE-1 protein levels were measured by western blot, and results analysed before and after adjustment for factor VIII-related antigen. Results: We showed ECE-1 to be in vascular endothelial cells. We did not find significant differences in ECE-1 mRNA or protein levels (either full-length ECE-1 or the soluble spliced variant, ECE-1sv) in AD or VaD compared with controls. Conclusions: Our findings suggest that any disease-specific contribution of ECE-1 to the accumulation of A beta or reduction in local microvascular blood flow in AD or VaD is probably small, with abnormal production of ET-1 being more likely to reflect A beta-mediated upregulation of ECE-2.
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