期刊
ALZHEIMERS & DEMENTIA
卷 10, 期 5, 页码 S411-S419出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2013.11.004
关键词
Aging; Animal model; Brain disorder; CNS; Dementia; Demyelination; Drug trial; Liver damage; Human studies; Melatonin; Neuronal death; Sialylation; Secretase; Side effects; ROS
资金
- Alzheimer's Association (Zenith Award and IIRG)
- National Institutes of Health [AG18379, AG18884, AG042804]
- Intramural Research Program of the National Institute on Aging, NIH
Alzheimer's disease (AD) is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide (A beta). The rate-limiting step in the production of Ab is the processing of A beta precursor protein (APP) by beta-site APP-cleaving enzyme (BACE1). Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Ab within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I (STGal6 I). In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (C) 2014 The Alzheimer's Association. All rights reserved.
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