Analysis of Alzheimer disease mechanism using iPS derived human cortical neuro
- Conditions
- Alzheimer's Disease
- Registration Number
- JPRN-UMIN000024913
- Lead Sponsor
- Osaka University
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete: follow-up complete
- Sex
- All
- Target Recruitment
- 8
Not provided
other dementia than AD
Study & Design
- Study Type
- Observational
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method