The most recent publication from PREP lab, published in Science Translational Medicine, shows that PREP inhibition works also in the Tau-based models of neurodegenerative diseases, having even a disease-modifying effect on cognition.
PREP lab has earlier shown that PREP inhibition has good effect on Parkinson’s disease models that are based on alpha-synuclein accumulation, a protein that is known hallmark for Parkinson’s disease. In several dementia, a protein called Tau starts to aggregate, damages neurons and eventually leads to neuronal death. This is seen in Alzheimer’s disease and in a group of other dementias called tauopathies, that include e.g. frontotemporal dementia. This makes Tau a tempting drug target. Since Tau aggregation shares certain similarities with alpha-synuclein, we wanted to test if PREP inhibitors have effect on Tau aggregation as well.
We were able to show that PREP interacts with Tau directly, and similar to alpha-synuclein, this leads to enhanced Tau aggregation. However, PREP inhibitor can block this effect, and activate cellular mechanisms that lead to stabilization of Tau and to degradation of Tau aggregates. In cellular model, PREP inhibition increased the cell survival, and significant impact on Tau aggregation was also seen in frontotemporal dementia patient derived cells that were differentiated as neurons. Finally, 4-week PREP inhibition was tested in a mouse model of frontotemporal dementia. The treatment was started when mice already had problems in memory and learning, and surprisingly, after the PREP inhibitor treatment, the mice had restored normal learning abilities. Moreover, tau accumulation in the brain and also in the CSF had restored to control levels. This gives high promise to take small-molecular PREP modulators further in the drug development also in dementia.
Link to publication: https://www.science.org/stoken/author-tokens/ST-1173/full