New target for Alzheimer’s drugs

Discovery of how certain small molecules — with promising properties for the treatment Alzheimer’s disease — operate could lead to new drugs for Alzheimer’s and other diseases.

A hallmark of Alzheimer’s disease is the accumulation of amyloid-beta peptide that forms plaques in the brain. The so-called 42-residue form of amyloid-beta peptide, or Aβ42, is created when an enzyme called gamma-secretase cleaves a larger precursor protein, APP.

Thomas Kukar from the Mayo Clinic College of Medicine, USA, and colleagues from the USA, Switzerland, Germany and Ireland, report in Nature this week that some gamma-secretase modulators (GSMs) work by directly targeting the APP substrate rather than the enzyme itself. Importantly, the team has found that as well as reducing the production of Aβ42, these GSMs stop proteins from aggregating.

The researchers say their work provides proof-of-principle for a new family of substrate-targeted drugs for Alzheimer’s and other diseases.

According to Thomas Kodadek from the University of Texas Southwestern Medical Center, USA, in a related ‘News & Views’ article, substrate-targeted drugs are an attractive prospect, because they are expected to be much more selective for their proteins than protease-targeted inhibitors could be.