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: ℗Tau [1 – 4] and ℗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 ℗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 ℗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

TBA