Why So Many Alzheimer’s Drugs Have Failed

Scientists in Japan have demonstrated why drugs targeting the enzyme that produces the protein plaques in Alzheimer’s disease patients fail in clinical trials.

AsianScientist (Nov. 3, 2017) – A team of researchers from Osaka University has shown that an inhibitor molecule meant to suppress the production of protein plaques in Alzheimer’s disease patients may in fact exacerbate the accumulation of those plaques in brain cells. Their findings, published in Cell Reports, could explain why many initially promising Alzheimer’s drugs have failed at the clinical stage.

Amyloid-β peptide (Aβ) accumulates in the brain at the very early stages of Alzheimer’s disease. Since the generation of Aβ is based on the activity of the enzyme γ-secretase, nearly 50 clinical trials have targeted γ-secretase inhibitors. However, all of these trials have failed, except for two studies which are currently ongoing.

In this study, scientists at Osaka University found that some potential γ-secretase inhibitors, which have been used in large clinical trials that ended in failure, do not function as true inhibitors as originally expected. Rather, such inhibitors cause the accumulation of toxic intraneuronal Aβ.

The researchers proved this by measuring the amount of direct products of γ-secretase within cells, which are peptides of three to five amino-acid residues, named γ-byproducts. Non-transition state analog γ-secretase inhibitors, including semagacestat, increased the levels of γ-byproducts.

“In our assay, we found γ-byproducts in the cell membrane. Semagacestat may prevent the release of γ-byproducts from the membrane, but not the generation of γ-byproducts,” said study corresponding author Associate Professor Masayasu Okochi.

The researchers also examined the amount of Aβ inside neurons. Although semagacestat did in fact decrease the amount of secreted Aβ, as has been previously reported, Aβ was found to accumulate inside neurons derived from human induced pluripotent stem cells and various types of cultured cells.

Clinical tests of semagacestat tended to judge the drug based on Aβ secretion but not γ-byproducts. The results of this study thus provide an explanation for why the clinical trials for Alzheimer’s disease drugs have failed, shedding new light on the discord between preclinical and clinical findings.

“Our tests suggest that molecularly targeted therapy should be thoroughly checked from all angles before proceeding 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,” said Okochi.



The article can be found at: Tagami et al. (2017) Semagacestat Is a Pseudo-Inhibitor of γ-Secretase.

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Source: Osaka University; Photo: Shutterstock.
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