Alzheimer's disease beta-amyloid peptide is increased in mice deficient in endothelin-converting enzyme.
The abnormal accumulation of beta-amyloid (Abeta) in the brain is an early and invariant feature in Alzheimer's disease (AD) and is believed to play a pivotal role in the etiology and pathogenesis of the disease. As such, a major focus of AD research has been the elucidation of the mechanisms responsible for the generation of Abeta. As with any peptide, however, the degree of Abeta accumulation is dependent not only on its production but also on its removal. In cell-based and in vitro models we have previously characterized endothelin-converting enzyme-1 (ECE-1) as an Abeta-degrading enzyme that appears to act intracellularly, thus limiting the amount of Abeta available for secretion. To determine the physiological significance of this activity, we analyzed Abeta levels in the brains of mice deficient for ECE-1 and a closely related enzyme, ECE-2. Significant increases in the levels of both Abeta40 and Abeta42 were found in the brains of these animals when compared with age-matched littermate controls. The increase in Abeta levels in the ECE-deficient mice provides the first direct evidence for a physiological role for both ECE-1 and ECE-2 in limiting Abeta accumulation in the brain and also provides further insight into the factors involved in Abeta clearance in vivo.
Eckman
Elizabeth A
EA
Mayo Clinic Jacksonville, Florida 32224, USA. Eckman@mayo.edu
Watson
Mona
M
Marlow
Laura
L
Sambamurti
Kumar
K
Eckman
Christopher B
CB
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000502:physiology*; D015153:Blotting, Western; D000072396:Endothelin-Converting Enzymes; D004797:Enzyme-Linked Immunosorbent Assay; D008666:Metalloendopeptidases; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; C000606926:Ece2 protein, mouse; D000072396:Endothelin-Converting Enzymes