Frontotemporal dementias (FTDs) are an umbrella term for diseases, where the patient has variable symptoms in memory, cognition and behavior, and brain atrophy is focused on certain frontal brain areas. The onset of the disease is usually earlier than with Alzheimer’s disease, the most common cause of dementia, and FTDs are the most common dementia for working-aged people. Unfortunately, there is no effective therapies available, and even commonly used Alzheimer’s disease therapies have no effect on FTDs. Therefore, it is critical to develop and test novel therapies for FTDs.

It is not clear what causes neuronal death in FTD patient brain, but a protein called Tau is commonly find to be accumulated in FTD patient brain. Tau is also present in Alzheimer’s disease, and common hypothesis is that Tau eventually drives the neuronal death. Therefore, Tau accumulation could be a good drug target also in FTD, and several approaches has been tried to reduce Tau burden in FTD patient brain. However, these have not been yet successful.

An enzyme called protein phosphatase 2A (PP2A) is the main regulator for Tau. Reduced PP2A activity is seen in FTDs but its re-activation has been difficult.

Our approach to re-active PP2A and thus reduce Tau accumulation in brain, is to modify prolyl oligopeptidase (PREP) that is a fine-tuning regulator of PP2A activity, by a PREP-specific ligand. We have already successfully shown in a FTD mouse model that PREP ligand treatment removes excess Tau in the mouse brain and restores is cognitive abilities. However, the ligand needs some modifications in order to progress to further studies, including clinical trials, and our project aims to find the best PREP ligand to tackle Tau accumulation in FTD.