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Open Access 01-12-2024 | Pathology | Research

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

Authors: Dominika Olešová, Dana Dobešová, Petra Majerová, Radana Brumarová, Aleš Kvasnička, Štěpán Kouřil, Eva Stevens, Jozef Hanes, Ľubica Fialová, Alena Michalicová, Juraj Piešťanský, Jakub Šinský, Petr Kaňovský, David Friedecký, Andrej Kováč

Published in: Journal of Neuroinflammation | Issue 1/2024

Abstract

Background

Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer’s disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood.

Methods

We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation.

Results

We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism.

Conclusion

Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

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Title: Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies
Authors: Dominika Olešová
Dana Dobešová
Petra Majerová
Radana Brumarová
Aleš Kvasnička
Štěpán Kouřil
Eva Stevens
Jozef Hanes
Ľubica Fialová
Alena Michalicová
Juraj Piešťanský
Jakub Šinský
Petr Kaňovský
David Friedecký
Andrej Kováč
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Pathology
Published in: Journal of Neuroinflammation / Issue 1/2024
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-024-03060-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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