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Published online before print June 18, 2009
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From the Dementia Research Group, Frenchay Hospital, Clinical Science at North Bristol, University of Bristol, Bristol, United Kingdom
Alzheimer’s disease (AD) is thought to be caused by the accumulation of amyloid beta (Aβ) peptide within the brain. Endothelin-converting enzyme-2 (ECE-2), which is expressed in neural tissues, cleaves ‘big endothelin’ to produce the vasoconstrictor endothelin-1. ECE-2 also degrades Aβ. We have examined ECE-2 expression in the temporal cortex of brain tissue from patients with AD, vascular dementia, and controls. Immunohistochemistry with specific antibodies showed ECE-2 to be abundant within pyramidal neurons in both the hippocampus and neocortex, but also to be present in certain astrocytes and microglia, particularly in AD brains. Quantitative real-time PCR showed ECE-2 mRNA to be markedly elevated in AD but not in vascular dementia. ECE-2 protein concentration, measured by sandwich enzyme-linked immunosorbent assay, was also significantly elevated in AD but not in vascular dementia. Exposure of SH-SY5Y human neuroblastoma cells to monomeric or oligomeric Aβ1–42 caused an initial decrease in ECE-2 mRNA at 4 hours, but a marked increase by 24 hours. Our findings indicate that Aβ accumulation in AD is unlikely to be caused by ECE-2 deficiency. However, ECE-2 expression is up-regulated, perhaps to minimize Aβ accumulation, but this may also be a mechanism through which endothelin-1 production is increased and cerebral blood flow is reduced in AD. Our findings suggest that endothelin-1 receptor antagonists, already licensed for treating other diseases, could be of benefit in AD therapies.
Related Article
Am. J. Pathol. 2009 175: 1-2.
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