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The Journal of Neuroscience, August 8, 2007, 27(32):8628-8635; doi:10.1523/JNEUROSCI.1549-07.2007

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Neurobiology of Disease
Angiotensin-Converting Enzyme Converts Amyloid ß-Protein 1–42 (Aß_1–42) to Aß_1–40, and Its Inhibition Enhances Brain Aß Deposition

Kun Zou,^1,3 Haruyasu Yamaguchi,⁴ Hiroyasu Akatsu,⁵ Takaaki Sakamoto,¹ Mihee Ko,¹ Kazushige Mizoguchi,² Jian-Sheng Gong,¹ Wenxin Yu,¹ Takayuki Yamamoto,⁵ Kenji Kosaka,⁵ Katsuhiko Yanagisawa,¹ and Makoto Michikawa¹

Departments of ¹Alzheimer's Disease Research and ²Geriatric Medicine, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8522, Japan, ³Japan Society for the Promotion of Science, Tokyo 102-8471, Japan, ⁴Gunma University School of Health Sciences, Maebashi 371-8514, Japan, and ⁵Choju Medical Institute, Fukushimura Hospital, Toyohashi 441-8124, Japan

Correspondence should be addressed to Dr. Makoto Michikawa, Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. Email: michi{at}nils.go.jp

The abnormal deposition of the amyloid ß-protein (Aß) in the brain appears crucial to the pathogenesis of Alzheimer's disease (AD). Recent studies have suggested that highly amyloidogenic Aß_1–42 is a cause of neuronal damage leading to AD pathogenesis and that monomeric Aß_1–40 has less neurotoxicity than Aß_1–42. We found that mouse and human brain homogenates exhibit an enzyme activity converting Aß_1–42 to Aß_1–40 and that the major part of this converting activity is mediated by the angiotensin-converting enzyme (ACE). Purified human ACE converts Aß_1–42 to Aß_1–40 as well as decreases Aß_1–42/Aß_1–40 ratio and degrades Aß_1–42 and Aß_1–40. Importantly, the treatment of Tg2576 mice with an ACE inhibitor, captopril, promotes predominant Aß_1–42 deposition in the brain, suggesting that ACE regulates Aß_1–42/Aß_1–40 ratio in vivo by converting secreted Aß_1–42 to Aß_1–40 and degrading Aßs. The upregulation of ACE activity can be a novel therapeutic strategy for AD.

Key words: angiotensin-converting enzyme; ACE; Alzheimer's disease; amyloid ß-protein; Aß; Aß deposition; Aß degradation; APP transgenic mouse

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Received Dec. 23, 2006; revised June 11, 2007; accepted June 29, 2007.

Correspondence should be addressed to Dr. Makoto Michikawa, Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. Email: michi{at}nils.go.jp

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