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Angiotensin-converting enzyme converts amyloid β-protein 1-42 (Aβ1-42) to Aβ1-40, and its inhibition enhances brain Aβ deposition


Year of Publication:
Contact PI Name:
Makoto Michikawa
Contact PI Affiliation:
Department of Alzheimer’s Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Japan
Kun Zou, Haruyasu Yamaguchi, Hiroyasu Akatsu, Takaaki Sakamoto, Mihee Ko, Kazushige Mizoguchi, Jian-Sheng Gong, Wenxin Yu, Takayuki Yamamoto, Kenji Kosaka, Katsuhiko Yanagisawa
Primary Reference (PubMED ID):
Funding Source:
Japanese Ministry of Health, Labour and Welfare
Program for Promotion of Fundamental Studies in Health of the National Institute of Biomedical Innovation
Japan Society for the Promotion of Sciences (JSPS)
Study Goal and Principal Findings:

The abnormal deposition of the amyloid β-protein (Aβ) in the brain appears crucial to the pathogenesis of Alzheimer’s disease (AD). Recent studies have suggested that highly amyloidogenic Aβ1– 42 is a cause of neuronal damage leading to AD pathogenesis and that monomeric Aβ1– 40 has less neurotoxicity than Aβ1– 42. They found that mouse and human brain homogenates exhibit an enzyme activity converting Aβ1– 42 to Aβ1– 40 and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts Aβ1– 42 to Aβ1– 40 as well as decreases Aβ1– 42/Aβ1– 40 ratio and degrades Aβ1– 42 and Aβ1– 40. Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant Aβ1– 42 deposition in the brain, suggesting that ACE regulates Aβ1– 42/Aβ1– 40 ratio in vivo by converting secreted Aβ1– 42 to Aβ1– 40 and degrading Aβs. The upregulation of ACE activity can be a novel therapeutic strategy for AD.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Angiotensin I Converting Enzyme (ACE)
Therapeutic Notes:
Angiotensin I converting enzyme has been nominated as a potential target for AD. Nominated targets are obtained from several sources, including the National Institute on Aging's Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) consortium. Targets have been identified using computational analyses of high-dimensional genomic, proteomic and/or metabolomic data derived from human samples. See Agora link for more information.

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Not Reported

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Dense-core/Compact Plaques
Brain-beta Amyloid Peptide 42
Brain-beta Amyloid Peptide 40
Angiotensin Converting Enzyme (ACE)
Angiotensin Converting Enzyme (ACE) Activity
beta Amyloid Aggregation
Brain-beta Amyloid Peptide 40
Brain-beta Amyloid Peptide 42
Target Engagement (Inhibition Angiotensin Converting Enzyme )