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Dissolving Protein Deposits In The Brain


Tauopathies are neurodegenerative diseases in which tau proteins accumulate in the brain. More than 20 different diseases, such as Alzheimer's and frontotemporal dementia, fall into this category. In collaboration with researchers from Finland, a team led by Prof. Dr Gert Fricker from the Institute of Pharmacy and Molecular Biotechnology at Heidelberg University investigated whether inhibiting an associated enzyme could protect against tau's damaging effects. The studies suggest that using a special inhibitor could reduce the progressive damage to the brain in tauopathies.

The tau protein is a vital structural protein in the brain that stabilises nerve cells. It supports the transport of nutrients and other materials into the cells. In neurodegenerative diseases like Alzheimer's and frontotemporal dementia, however, altered forms of the tau protein arise called hyperphosphorylated tau proteins. Phosphate groups bind to the protein, causing it to lose its function and accumulate as filaments and deposits. These deposits disrupt the function of the nerve cells, leading to a progressive loss in brain function. Using cellular in-vitro models and a transgenic mouse model, Prof. Fricker's research team investigated whether inhibiting an enzyme known as PREP would protect against tau's toxic effects.

PREP is a serine protease, an enzyme that can split proteins and peptides and is associated with neurodegeneration. When PREP was blocked by an inhibitor, the deposit of tau protein in the cells was reduced. In addition, the clearance of insoluble tau improved. In a mouse model of frontotemporal dementia, PREP inhibition was able to alleviate symptoms of the disease and restore normal cognitive abilities. The researchers also noted a reduction in oxidative stress in the brain. "Our study thereby suggests that PREP inhibition can help reduce the neurodegenerative damage in the brain due to tauopathies", states Prof. Fricker. The current investigations are part of an international cooperation between Dr Elena Puris and Dr Mikko Gynther of Prof. Fricker's team at the Institute of Institute of Pharmacy and Molecular Biotechnology at Heidelberg University and the research team of pharmacologist Prof. Dr Timo Myöhänen of the University of Helsinki. The results of the research were published in the journal “Science Translational Medicine”.

ORIGINAL PUBLICATION T. S. Eteläinen, M. C. Silva, J. K. Uhari-Väänänen, F. De Lorenzo, M. H. Jäntti, H. Cui, M. Chavero-Pieres, T. Kilpeläinen, C. Mechtler, R. Svarcbahs, E. Seppälä, J. R. Savinainen, E. Puris, G. Fricker, M. Gynther, U. H. Julku, H. J. Huttunen, S. J. Haggarty, T. T. Myöhänen: A prolyl oligopeptidase inhibitor reduces tau pathology in cellular models and in mice with tauopathy, in: Science Translational Medicine, 15 (691), (12 Apr 2023).

  • DOI: 10.1126/scitranslmed.abq2915


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