Endothelin-converting enzyme-2 is increased in Alzheimer's disease and up-regulated by Abeta.
Alzheimer's disease (AD) is thought to be caused by the accumulation of amyloid beta (Abeta) 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 Abeta. 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 Abeta(1-42) caused an initial decrease in ECE-2 mRNA at 4 hours, but a marked increase by 24 hours. Our findings indicate that Abeta accumulation in AD is unlikely to be caused by ECE-2 deficiency. However, ECE-2 expression is up-regulated, perhaps to minimize Abeta 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.
Palmer
Jennifer C
JC
Dementia Research Group, Frenchay Hospital, Bristol, United Kingdom. jen.palmer@bristol.ac.uk
Baig
Shabnam
S
Kehoe
Patrick G
PG
Love
Seth
S
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D016229:Amyloid beta-Peptides; D012333:RNA, Messenger; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606924:ECE2 protein, human; D000072396:Endothelin-Converting Enzymes