PREP inhibitors reduce Tau buildup and restore memory in dementia models, making it a promising candidate for future drug development.
Scientists from the University of Helsinki have successfully demonstrated that a compound known as a PREP inhibitor can prevent the build-up of a harmful protein responsible for memory disorders, among other things.
This harmful protein buildup, similar to that seen in Parkinson’s disease, is also observed in Alzheimer’s disease and other types of dementia. This process involves the formation of b-amyloid plaques and Tau protein aggregates within brain cells, which are known as neurofibrillary tangles. The prevailing theory suggests that the creation of Tau aggregates ultimately leads to the death of neurons.
The amount of Tau present aligns closely with the severity of clinical symptoms. Tau plays a critical role, particularly in a group of dementias known as Tauopathies, which include conditions like frontotemporal dementia.
In a freshly published paper, Professor Timo Myöhänen’s group from the Universities of Helsinki and Eastern Finland showed that a PREP inhibitor reduces Tau accumulation and toxicity also in the cellular models, including patient-derived neurons from frontotemporal dementia patients.
After promising cellular results, PREP inhibitor treatment was also tested in a mouse model of frontotemporal dementia. To follow the clinical situation, one-month treatment with the PREP inhibitor was initiated by the time of memory impairment. After treatment, mice that received the control treatment were performing poorly in a memory test, but mice treated with the PREP inhibitor had normal cognitive skills.
“Our most important discovery was that the PREP inhibitor treatment had reduced Tau accumulation in the brain areas related to cognition and memory, also leading to reduced oxidative stress markers that are common in neurodegenerative diseases,” says Professor Timo Myöhänen.
“The results from the memory tests after PREP inhibitor treatment were surprisingly good, as treatments in similar studies are usually initiated before the symptoms, not after symptom onset. This supports the further development of PREP-targeting drugs, and we are currently looking for investors or collaborators for this”, Professor Myöhänen says.
Reference: “A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy” by Tony S. Eteläinen, M. Catarina Silva, Johanna K. Uhari-Väänänen, Francesca De Lorenzo, Maria H. Jäntti, Hengjing Cui, Marta Chavero-Pieres, Tommi Kilpeläinen, Christina Mechtler, Reinis Svarcbahs, Erin Seppälä, Juha R. Savinainen, Elena Puris, Gert Fricker, Mikko Gynther, Ulrika H. Julku, Henri J. Huttunen, Stephen J. Haggarty and Timo T. Myöhänen, 12 April 2023, Science Translational Medicine.
DOI: 10.1126/scitranslmed.abq2915
The research was mainly performed in Professor Myöhänen’s research groups at the Universities of Helsinki and Eastern Finland, and groups from Harvard University, USA, and the University of Heidelberg, Germany, also participated in the study.
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