Tau oligomers and stress granules: Molecular insights into slowly and rapidly progressive Alzheimer’s disease

Tau oligomers and stress granules: Molecular insights into slowly and rapidly progressive Alzheimer’s disease

by Tayyaba Saleem
Doctoral thesis
Date of Examination:2025-05-13
Date of issue:2025-05-27
Advisor:Prof. Dr. Inga Zerr
Referee:PD Dr. Michael Hoppert
Referee:Prof. Dr. Inga Zerr
Persistent Address: http://dx.doi.org/10.53846/goediss-11283

 

 

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Abstract

English

Alzheimer’s disease (AD) exhibits substantial clinical and molecular heterogeneity, with rapidly progressive AD representing a distinct and aggressive subtype. This study provides an in-depth characterization of stress granules (SGs) and tau oligomers (TauO) in AD subtypes, uncovering their molecular interplay and contribution to disease progression. Through biochemical fractionation, immunoprecipitation, and mass spectrometry we identified distinct SG proteome in slowly progressive AD (spAD) and rpAD, revealing subtype specific compositional differences. Transmission electron microscopy (TEM) further demonstrated that rpAD-associated SGs exhibit increased aggregation, altered morphology and greater association with lysosomal structures, suggesting impaired clearance mechanisms. Proteomic analysis of SGs in rpAD highlighted differential enrichment of proteins involved in cytoskeletal organization, ribonucleoprotein assembly and metabolic processes suggesting dysfunction of related processes. RNA sequencing of SG-associated transcripts highlighted a widespread depletion of several crucial RNA species linked to neurodegeneration particularly in rpAD, including those involved in synaptic function, protein translation and RNA metabolism. Concurrently, TauO characterization revealed that rpAD cases exhibit distinct phosphorylation pattern through post translational modifications (PTMs) at serine 396 and serine 422, and enhanced neurotoxicity in neuronal models compared to spAD. Mass spectrometry-based interactome analysis showed a significant overlap between SG proteome and potential TauO interactors, supporting a mechanistic link between tau pathology and SG dysfunction in AD. Notably, rpAD exhibited a higher number of unique TauO interactors than spAD, underscoring the presence of subtype-specific molecular signatures. Functional enrichment analysis identified shared molecular pathways between SGs and TauO emphasizing RNA-binding, protein quality control and metabolic dysregulation as key drivers of rapid disease progression. Ultimately, integration of multi-omics datasets revealed that rpAD is characterized by hyper aggregated state, defective SG clearance, and toxic tau species that likely accelerate disease progression. This study provides crucial insights into the molecular signatures distinguishing AD subtypes.
Keywords: Ribonucleoproteins (RNPs), rapidly progressive Alzheimer’s disease, TIA-R, stress granules, Tau Oligomers