Published online before print June 18, 2009

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.081054

Accepted for publication March 17, 2009.

Article

Endothelin-Converting Enzyme-2 Is Increased in Alzheimer's Disease and Up-Regulated by A

From the Dementia Research Group, Frenchay Hospital, Clinical Science at North Bristol, University of Bristol, Bristol, United Kingdom

^@ To whom correspondence should be addressed. E-mail: jen.palmer{at}bristol.ac.uk.

	Abstract

Alzheimer's disease (AD) is thought to be caused by the accumulation of amyloid beta (A) 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 A. 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 A_1–42 caused an initial decrease in ECE-2 mRNA at 4 hours, but a marked increase by 24 hours. Our findings indicate that A accumulation in AD is unlikely to be caused by ECE-2 deficiency. However, ECE-2 expression is up-regulated, perhaps to minimize A 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.