Picking the best isoform: PDE4D isoforms as therapeutic targets in Alzheimer’s disease

Previous research has shown potential for medicines that block the action of PDE4D enzymes, which comprise 9 forms, to enhance memory function in Alzheimer’s disease. However, this medicine, called PDE4D inhibitors, can cause severe side effects. In this thesis, two treatment strategies are demonstrated by which PDE4D enzymes can be blocked that potentially do not cause side effects. ‘Conventional’ inhibitors block all 9 forms of the PDE4D family, but this thesis indicated that blocking single specific forms is sufficient to stimulate memory formation processes. This finding allows for the development of more specific medicines (that cause fewer/no side effects). The other strategy provided in this thesis showed that when conventional PDE4D inhibitors are combined with another class of medicine, the required dose of the PDE4D inhibitor to improve memory in mice is lower. A lower dose will also reduce the risk of side effects. Thus, these two new, promising strategies await to be validated in patients for safe and effective memory improvement.