Servicenavigation

Project Details

Back

Projekt Print View

Towards a high-resolution picture of the stability of protein deposits and its modulation in neurodegenerative diseases: visualizing the invisible by fluorine NMR dynamics

Subject Area Structural Biology
Biophysics
Term from 2016 to 2025
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 327959918
 
Final Report Year 2024

Final Report Abstract

As the most common cause of dementia, Alzheimer’s disease (AD) imposes growing burden on our ageing societies. The progressive clinical course of AD is preceded by a long prodromal preclinical phase, during which the neuropathological hallmarks of AD, e.g. extracellular deposition of amyloid-β (Aβ) peptide, gradually develop. Several lines of evidence point to the key role of Aβ aggregation as the initial triggering event in AD pathogenesis. A remarkable feature of AD is the high level of heterogeneity in its neuropathological and clinical course, for which the exact underlying molecular factors are not well understood. In this project, first, we developed a new integrative approach combining NMR and other biophysical techniques and provided a detailed picture of dynamics in Aβ monomers, which highlighted the crucial importance of a kinetic balance between various modes of Aβ motions for its aggregation and served as a reference for further mechanistic studies in this project. Second, we provided evidence for the mechanistic role of two short segments of Aβ in its early aggregation, the Gly33-Leu34-Met35 segment in the C-terminal part and Arg5-based salt bridges in the N-terminal part, and suggested them as potential druggable targets in anti-AD drug development. Third, we demonstrated through high-pressure NMR that some mutations in Aβ (E22G, D23N and ΔE22) alter the pressure stability of Aβ fibrils in drastically different ways and proposed “stability variation” as a molecular property potentially contributing to the remarkable neuropathological diversity in familial AD. Fourth, we showed that pressure stability of Aβ fibrils is altered during in vitro ageing and suggested that “stability maturation” of Aβ fibrils should be taken into consideration in development of molecular imaging probes against Aβ fibrils. Fifth, through mathematical modelling, we showed that the coupled Aβ aggregation-inflammation system has a high tendency for sustained oscillations and suggested that such sustained oscillations might mark the transition to a more progressive phase of amyloid pathology in preclinical AD, hence potentially used as an early biomarker of AD. Further mechanistic insight on Aβ aggregation will be provided upon completion of fluorine NMR data analysis. Besides, our project led to some NMR method developments, especially in the areas of quadrupolar, singlet-state and fluorine NMR, which were applied to deciphering peptide, water and ion dynamics and component exchange kinetics in systems undergoing aggregation and phase separation.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung