| Autor: |
Shinji Tagami, Kanta Yanagida, Takashi S. Kodama, Mako Takami, Naoki Mizuta, Hiroshi Oyama, Kouhei Nishitomi, Yu-wen Chiu, Toru Okamoto, Takeshi Ikeuchi, Gaku Sakaguchi, Takashi Kudo, Yoshiharu Matsuura, Akio Fukumori, Masatoshi Takeda, Yasuo Ihara, Masayasu Okochi |
| Jazyk: |
angličtina |
| Rok vydání: |
2017 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 21, Iss 1, Pp 259-273 (2017) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2017.09.032 |
| Popis: |
γ-secretase inhibitors (GSI) are drugs developed to decrease amyloid-β peptide (Aβ) production by inhibiting intramembranous cleavage of β-amyloid protein precursor (βAPP). However, a large phase 3 trial of semagacestat, a potential non-transition state analog (non-TSA) GSI, in patients with Alzheimer’s disease (AD) was terminated due to unexpected aggravation of cognitive deficits and side effects. Here, we show that some semagacestat effects are clearly different from a phenotype caused by a loss of function of presenilins, core proteins in the γ-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Aβ through serial γ-cleavage of βAPP, as well as intracellular long Aβ species, in cell-based and in vivo studies of AD model mice. Other potential non-TSA GSIs, but not L685,458, a TSA GSI, have similar effects. Furthermore, semagacestat inhibits release of de novo intramembranous γ-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Aβ hypothesis. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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