Why do Alzheimer's drugs work in the lab but not in patients?


By LabOnline Staff
Tuesday, 31 October, 2017


Dollarphotoclub 52167869

Japanese researchers have been investigating the reasons why so many trials of drugs for Alzheimer’s disease fail, particularly after they have shown promise in the lab. Their study provides an explanation for why clinical trials for Alzheimer’s disease drugs have failed and gives new light on the discord between preclinical and clinical findings.

A tremendous amount of Amyloid-β peptide (Aβ, a peptide of ~40 amino acids) accumulates in the brain of Alzheimer’s disease patients, beginning in the very early stages of the disease. As noted by Osaka University Associate Professor Masayasu Okochi, “Aβ generation is based on the activity of presenilin/γ-secretase, which mediates the cellular production of Aβ.”

Among the promising sets of drugs for Alzheimer’s disease are γ-secretase inhibitors like semagacestat, designed to inhibit the enzymatic activity that produces Aβ. By reducing Aβ production, γ-secretase inhibitors were considered able to treat Alzheimer’s disease, in what was called the Aβ hypothesis. 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. One of the most infamous examples is a clinical trial that began almost 10 years ago and was terminated early. Not only was semagacestat found to fail, but 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 the finding, Okochi and his colleagues sought to discover whether semagacestat really is a β-secretase inhibitor that inhibits the target function, ie, the cleavage performed by γ-secretase (γ-cleavage). To do so, they established an original method which can measure direct products of γ-secretase (peptides of 3–5 small amino-acid residues, which were named γ-byproducts). The results were published in the journal Cell Reports.

Surprisingly, non-transition state analogue γ-secretase inhibitors including semagacestat did not decrease, but rather increased the levels of γ-byproducts. This finding shattered the belief that these compounds truly inhibit the proteolytic function of γ-secretase and made the researchers ‘look’ inside neurons for further assessment. As predicted from the increased level of γ-byproducts, an accumulation of toxic intraneuronal 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 to Okochi that semagacestat is not in fact a γ-secretase inhibitor, but rather a “pseudo γ-secretase inhibitor”, as it is described in the study. Clinical tests of semagacestat tended to judge the drug based on Aβ secretion but not γ-byproducts, the researchers explained, which could explain why pseudo γ-secretase inhibitors have been repeatedly mislabelled.

“We found the type of assay gives different results,” Okochi said. “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.”

Ironically, Okochi claims the failed clinical trials actually affirm the Aβ hypothesis.

“I believe normalisation of production and secretion of Aβ by sharpening γ-secretase is the right approach to treating Alzheimer’s disease,” he said. “Our tests suggest that molecularly targeted therapy should be thoroughly checked from all angles before its application to clinical studies. The new function of γ-secretase suggested in this study needs further analysis, which will contribute to the development of truly effective drugs for Alzheimer’s disease and several types of cancer.”

Image credit: ©darren whittingham/Dollar Photo Club

Related Articles

CRISPR-carrying nanoparticles can edit the genome

MIT researchers have developed nanoparticles that can deliver the CRISPR genome-editing system...

It was the killer T cells, on the cell surface, with granzyme B

It is well known in the scientific community that immune cells called cytotoxic lymphocytes, or...

Acid reflux drugs claimed to double stomach cancer risk

The long-term use of proton pump inhibitors (PPIs), a class of drugs commonly used to treat acid...


  • All content Copyright © 2017 Westwick-Farrow Pty Ltd