Molecular and structural remodeling of stress granules in slowly and rapidly progressive Alzheimer's disease

Stress granules (SGs) are dynamic ribonucleoprotein condensates that modulate RNA metabolism during cellular stress. Although SG dysfunction has been increasingly linked to neurodegenerative diseases, their structural and molecular remodeling in Alzheimers disease (AD), particularly rapidly progressive AD (rpAD), remains poorly understood. Here, we present a comprehensive multi-omics characterization of SGs from postmortem frontal cortex tissues of control, slowly progressive AD (spAD), and rpAD subjects. SGs were immunoprecipitated using Anti-TIAR antibodies and analyzed via transmission electron microscopy (TEM), LCMS/MS-based proteomics, and RNA sequencing. Key protein findings were validated in human cortical brain homogenates and a 3xTg mouse model of A{beta} and tau pathology. TEM revealed disease-specific SG morphologies: small spherical granules in controls; moderate clustering in spAD; and large, amorphous aggregates in rpAD. Proteomic profiling identified 1,667 high-confidence SG-associated proteins, including RNA-binding proteins and disease-linked proteins such as MAPT, APP, and SNCA. SGs in rpAD were significantly enriched for pathways involved in MAPK signaling, proteostasis, and neuroinflammation, while showing reduced abundance of key cytoskeletal and translational regulators, such as TUBA1B and EEF1A2. Transcriptome analysis revealed widespread depletion of long, GC-rich, protein coding RNAs in rpAD SGs. Notably dynamic dysregulation of TUBA1B was also observed in the 3xTg mouse model and human cortical tissues, highlighting cytoskeletal vulnerability during disease progression. Together, these findings uncover profound structural and molecular remodeling of SGs in AD, with rpAD exhibiting a distinctive shift towards pathological SG composition and function. Our results highlight a link between SG alterations and aggressive AD subtypes, providing new mechanistic insights and suggesting new potential targets for therapeutic intervention.