A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice

  1. Kun Zou?,**3
  1. From the ?Department of Neuroscience, School of Pharmacy, Iwate Medical University, Yahaba 028-3694, Japan,
  2. the §Liaoning Provincial Key Laboratory of Behavior and Cognitive Neuroscience, Shenyang Medical College, Shenyang 110034, China,
  3. the ?Faculty of Health and Medical Sciences, Aichi Shukutoku University, Nagakute 480-1146, Japan,
  4. the Graduate School of Nutritional Sciences, Nagoya University of Arts and Sciences, Nisshin 470-0196, Japan, and
  5. the **Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan
  1. ?1 To whom correspondence may be addressed. E-mail: michi{at}med.nagoya-cu.ac.jp.
  2. ?2 To whom correspondence may be addressed. E-mail: hkomano{at}iwate-med.ac.jp.
  3. ?3 To whom correspondence may be addressed. E-mail: kunzou{at}med.nagoya-cu.ac.jp.
  1. Edited by Paul E. Fraser

Abstract

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/? mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

Footnotes

  • This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Grants-in-Aid for Young Scientists (B) 22700399 and 24700383; Grants-in-Aid for Scientific Research (C) 26430057 and 19K07846; Grant-in-Aid for Strategic Medical Science Research S1491001; and funds from the Daiko Foundation and the Hirose International Scholarship Foundation and from the Doctoral Startup Foundation of Liaoning Province 201601227, China. The authors declare that they have no conflicts of interest with the contents of this article.

  • Received October 25, 2018.
  • Revision received May 7, 2019.

Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.

Table of Contents

This Article

  1. The Journal of Biological Chemistry 294, 9760-9770.
  1. All Versions of this Article:
    1. RA118.006420v1
    2. 294/25/9760 (most recent)

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