科研之友
微信
新浪微博
Facebook
分享链接
摘要
Alzheimer's disease (AD) is associated with deposition of amyloid-beta (A beta) in the brain, which is reflected by low concentration of the A beta(1-42) peptide in the cerebrospinal fluid (CSF). The gamma-secretase inhibitor LY450139 (semagacestat) lowers plasma A beta(1-40) and A beta(1-42) in a dose-dependent manner but has no clear effect on the CSF level of these isoforms. Less is known about the potent gamma-secretase modulator E2012. Using targeted proteomics techniques, we recently identified several shorter A beta isoforms in CSF, such as A beta(1-16), which is produced by a novel pathway. In a Phase II clinical trial on AD patients, A beta(1-14), A beta(1-15) and A beta(1-16) increased several-fold during gamma-secretase inhibitor treatment. In the present study, 9 dogs were treated with a single dose of the gamma-secretase modulator E2012, the gamma-secretase inhibitor LY450139, or vehicle with a dosing interval of 1 week. The CSF A beta isoform pattern was analyzed by immunoprecipitation combined with MALDI-TOF mass spectrometry. We show here that A beta(1-15) and A beta(1-16) increase while A beta(1-34) decreases in response to treatment with the gamma-secretase inhibitor LY450139, which is in agreement with previous studies. The isoform A beta(1-37) was significantly increased in a dose-dependent manner in response to treatment with E2012, while A beta(1-39), A beta(1-40) and A beta(1-42) decreased. The data presented suggests that the gamma-secretase modulator E-2012 alters the cleavage site preference of gamma-secretase. The increase in A beta(1-37) may inhibit A beta(1-42) oligomerization and toxicity.
- 出版日期2010
