| First Author | Tagami S | Year | 2017 |
| Journal | Cell Rep | Volume | 21 |
| Issue | 1 | Pages | 259-273 |
| PubMed ID | 28978478 | Mgi Jnum | J:254278 |
| Mgi Id | MGI:6104229 | Doi | 10.1016/j.celrep.2017.09.032 |
| Citation | Tagami S, et al. (2017) Semagacestat Is a Pseudo-Inhibitor of gamma-Secretase. Cell Rep 21(1):259-273 |
| abstractText | gamma-secretase inhibitors (GSI) are drugs developed to decrease amyloid-beta peptide (Abeta) production by inhibiting intramembranous cleavage of beta-amyloid protein precursor (betaAPP). 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 gamma-secretase complex. Semagacestat increases intracellular byproduct peptides, produced along with Abeta through serial gamma-cleavage of betaAPP, as well as intracellular long Abeta 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 gamma-byproducts to the soluble space. Thus, semagacestat is a pseudo-GSI, and therefore, the semagacestat clinical trial did not truly test the Abeta hypothesis. |
