Angiotensin-converting enzyme converts amyloid beta-protein 1-42 (Abeta(1-42)) to Abeta(1-40), and its inhibition enhances brain Abeta deposition.
The abnormal deposition of the amyloid beta-protein (Abeta) in the brain appears crucial to the pathogenesis of Alzheimer's disease (AD). Recent studies have suggested that highly amyloidogenic Abeta(1-42) is a cause of neuronal damage leading to AD pathogenesis and that monomeric Abeta(1-40) has less neurotoxicity than Abeta(1-42). We found that mouse and human brain homogenates exhibit an enzyme activity converting Abeta(1-42) to Abeta(1-40) and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts Abeta(1-42) to Abeta(1-40) as well as decreases Abeta(1-42)/Abeta(1-40) ratio and degrades Abeta(1-42) and Abeta(1-40). Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant Abeta(1-42) deposition in the brain, suggesting that ACE regulates Abeta(1-42)/Abeta(1-40) ratio in vivo by converting secreted Abeta(1-42) to Abeta(1-40) and degrading Abetas. The upregulation of ACE activity can be a novel therapeutic strategy for AD.
Zou
Kun
K
Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan.
Yamaguchi
Haruyasu
H
Akatsu
Hiroyasu
H
Sakamoto
Takaaki
T
Ko
Mihee
M
Mizoguchi
Kazushige
K
Gong
Jian-Sheng
JS
Yu
Wenxin
W
Yamamoto
Takayuki
T
Kosaka
Kenji
K
Yanagisawa
Katsuhiko
K
Michikawa
Makoto
M
D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016229:Amyloid beta-Peptides; D000806:Angiotensin-Converting Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D007703:Peptidyl-Dipeptidase A