Potential Alzheimer's Disease Drug Selectively Blocks Endosomal Beta-Secretase Activity

Beta-secretase inhibitors reduce A-beta levels, but mechanism-based side effects arise because they also inhibit beta-cleavage of non-amyloid substrates like neuregulin. The neuregulins are a family of four structurally related proteins that are part of the EGF (epidermal growth factor) family of proteins, which have been shown to have diverse functions in the development of the nervous system.

Investigators at the University of Zurich (Switzerland) and collaborators in Germany and India reported in the February 25, 2016, online edition of the journal Cell Reports that beta-secretase had a higher affinity for neuregulin than it did for APP. Kinetic studies demonstrated that the affinities and catalytic efficiencies of beta-secretase were higher toward non-amyloid substrates than toward APP.

The investigators took advantage of the fact that APP was cleaved by beta-secretase in endosome vesicles, while non-amyloid proteins were processed in other areas of the cell. This separation of activities allowed the investigators to specifically inhibit the endosomal beta-secretase with an endosomally targeted inhibitor. Inhibition of this enzyme blocked cleavage of APP, but not non-amyloid substrates, in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons.

Senior author Dr. Lawrence Rajendran, assistant professor of systems and cell biology of neurodegeneration at the University of Zurich, said, "The current beta secretase inhibitors do not just block the enzyme function that drives the course of Alzheimer's, but also physiologically important cell processes. Therefore, the substances currently being tested in clinical studies may also trigger nasty side effects - and thus fail."

"We managed to develop a substance that only inhibits beta secretase in the endosomes where the beta amyloid peptide forms. The specific efficacy of our inhibitor opens up a promising way to treat Alzheimer's effectively in future, without causing the patients any serious side effects," said Dr. Rajendran.

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