A tremendous amount of Amyloid-β peptide (Aβ) (a peptide of ~40 amino acids) accumulates in the brain of Alzheimer's disease patients. γ-Secretase inhibitors were designed to inhibit the enzymatic activity that produces Aβ. By reducing Aβ production, γ-secretase inhibitors were considered able to treat Alzheimer's disease (Aβ hypothesis). In fact, nearly 50 clinical trials have been conducted using potential γ-secretase inhibitors for Alzheimer's disease or several types of cancer. However, all of these trials have failed, except for two studies which are currently ongoing.

The scientists found that some potential γ-secretase inhibitors such as semagacestat, which have been used in large clinical trials that ended in failure, do not function as true inhibitors as originally expected, but rather cause accumulation of toxic intraneuronal Aβ. They proved this by introducing an original method to measure direct intracellular products of γ-secretase. They commented that the application of their evaluation method may help develop truly effective drugs for Alzheimer's disease (AD). The study can be seen in Cell Reports and provides an explanation for why the clinical trials for Alzheimer's disease drugs have failed and gives new light on the discord between preclinical and clinical findings.

"Aβ accumulates in the brain at the very early stages of Alzheimer's disease," the project lead. "Aβ generation is based on the activity of presenilin/γ-secretase which mediates the cellular production of Aβ."

Of the promising sets of drugs for Alzheimer's disease were γ-secretase inhibitors like semagacestat. However, a clinical trial that began almost 10 years ago was terminated early because not only was semagacestat found to fail, patient groups that received the drug showed exasperated symptoms compared to the placebo group. This finding has put great doubt into the Aβ hypothesis.

To understand this surprising finding, researchers considered whether semagacestat is indeed a γ-secretase inhibitor. In this study, they revealed that semagacestat does not really inhibit the target function, i.e., the cleavage performed by γ-secretase (γ-cleavage). What enabled them to reach this unexpected finding is an original method that this team established, which can measure direct products of γ-secretase (peptides of 3 to 5 small amino-acid residues which were named γ-byproducts).

As predicted from the increased level of γ-byproducts, an accumulation of Aβ was found inside neurons derived from human iPS cells and various types of cultured cells, although semagacestat did in fact decrease secreted Aβ, as has been previously reported.

These results suggested that semagacestat is not in fact a γ-secretase inhibitor, which is why they use the term "pseudo γ-secretase inhibitor" in the study. Clinical tests of semagacestat tended to judge the drug based on Aβ secretion but not γ-byproducts, which could explain why pseudo γ-secretase inhibitors have been repeatedly mislabeled.

"We found the type of assay gives different results. In our assay, we found γ-byproducts in the cell membrane. Semagacestat may prevent release of γ-byproducts from the membrane but not the generation of γ-byproducts," author said.

Ironically, the failed clinical trials and the findings affirm the Aβ hypothesis, author argues.

http://resou.osaka-u.ac.jp/en/research/2017/20171004_1

http://www.cell.com/cell-reports/abstract/S2211-1247(17)31307-4