Summary

J Biol Chem. 2019 Jun 21;294(25):9760-9770. doi: 10.1074/jbc.RA118.006420. Epub 2019 May 9.

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

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.

日本語要旨:

NILS-LSA参加者を対象とした8年間の縦断的検討で、降圧剤のACE阻害剤が知能の低下を招くことを明らかにした。また、マウスを使用した動物実験でACE阻害剤が脳のアミロイド蓄積を増加させることを示し、ACEの阻害が知能低下、アルツハイマー病の発症を招く可能性を明らかにした。

PMID:  31072831

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