Joseph Hritz

Title

Molecular mechanism of tau pathology in Alzheimer’s disease

Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), impose a significant burden on global health, affecting millions of individuals worldwide. ADDIT-CE, short for Alzheimer’s Disease Diagnostics Innovation and Translation to Clinical Practice in Central Europe, is a Horizon Europe Excellence Hubs project. It aims to connect research and innovation ecosystems in the Brno (South Moravia) and Bratislava regions through a joint cross-border strategy to modernize Alzheimer’s disease diagnostics and bring new approaches into clinical practice. The project brings together key innovation drivers—academia, industry, government, and society—to ensure impactful results.

Probably, the most significant hallmark in the brains of AD patients is neurofibrillary tangles (NFT) that are composed of multiple proteins, out of which two will be addressed in more detail in this presentation: (p)Tau [1-4] and (p)14-3-3s [5-7], including their phosphorylated variants. Over 80% of neuronal microtubule-associated proteins (MAPs) are composed of Tau protein. Tau protein is an intrinsically disordered protein that also plays a key role in AD. In the brains of AD patients, Tau occurs abnormally phosphorylated and aggregated in neurofibrillary tangles (NFTs). We aimed to reveal the effects of phosphorylation by protein kinase A (PKA) on Tau structural preferences and provide better insight into the interaction between Tau and 14-3-3 proteins [1,3,4].

Characterization of a soluble form of (p)Tau protein and its complexes has been performed by using multidimensional nuclear magnetic resonance spectroscopy (NMR) in combination with non-uniform sampling (NUS) [1,3]. It allowed differences in their binding affinity, stoichiometry, and interfaces with the single-residue resolution to be revealed, including proline residues. The fibril form of (p)Tau is characterized by cryoEM and solid-state NMR spectroscopy [2]. In addition, cryoEM tomography allows us to monitor the impact of Tau fibril formation on neurons within brain tissues.

In conclusion, we propose quite a complex interaction mode between the Tau and 14-3-3 proteins, combining NMR, cryoEM, and computational simulations.

References:

  1. S. Jansen et al. FEBS J. 2025; doi: 10.1111/febs.17405);
  2. K. Kitoka et al. Angew. Chem. Int. Ed. 2024, e202407821
  3. R. Crha et al.  Int. J. Biol. Macromol. 2024, 266, 130802
  4. A. Lasorsa et al. Biochemistry 2023, 62, 1631–1642
  5. A. Náplavová et al.  Int. J. Biol. Macromol. 2025, 305, 141253
  6. A. Kozeleková et al. Front. Chem. 2022, 10:835733
  7. Z. Trosanova et al. J. Mol. Biol. 2022, 434, 167479

Biography

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