Affiliation:
1. National Reference Center for Surveillance of TSE Department of Neurology University Medical Center Göttingen Göttingen Germany
2. German Center for Neurodegenerative Diseases (DZNE) Göttingen Germany
3. Department of Biological Sciences Faculty of Sciences University of Sialkot Sialkot Pakistan
4. Department of Biotechnology Faculty of Sciences University of Sialkot Sialkot Pakistan
5. Department of Pathology and Experimental Therapeutics University of Barcelona Hospitalet de Llobregat Spain
Abstract
AbstractAimsTau is a key player in Alzheimer's disease (AD) and other Tauopathies. Tau pathology in the brain directly correlates with neurodegeneration in AD. The recent identification of a rapid variant of AD demands an urgent need to uncover underlying mechanisms leading to differential progression in AD. Accordingly, we aimed to dissect the underlying differential mechanisms of toxicity associated with the Tau protein in AD subtypes and to find out subtype‐dependent biomarkers and therapeutic targets.MethodsTo identify and characterise subtype‐specific Tau‐associated mechanisms of pathology, we performed comparative interactome mapping of Tau protein in classical AD (cAD) and rapidly progressive AD (rpAD) cases using co‐immunoprecipitation coupled with quantitative mass spectrometry. The mass spectrometry data were extensively analysed using several bioinformatics approaches.ResultsThe comparative interactome mapping of Tau protein revealed distinct and unique interactors (DPYSL4, ARHGEF2, TUBA4A and UQCRC2) in subtypes of AD. Interestingly, an analysis of the Tau‐interacting proteins indicated enrichment of mitochondrial organisation processes, including negative regulation of mitochondrion organisation, mitochondrial outer membrane permeabilisation involved in programmed cell death, regulation of autophagy of mitochondrion and necroptotic processes, specifically in the rpAD interactome. While, in cAD, the top enriched processes were related to oxidation–reduction process, transport and monocarboxylic acid metabolism.ConclusionsOverall, our results provide a comprehensive map of Tau‐interacting protein networks in a subtype‐dependent manner and shed light on differential functions/pathways in AD subtypes. This comprehensive map of the Tau‐interactome has provided subsets of disease‐related proteins that can serve as novel biomarkers/biomarker panels and new drug targets.