Stress granules and tau pathology in Alzheimer's disease: A scoping review of bidirectional interactions, liquid-liquid phase separation, and proteostatic consequences.

BACKGROUND

Alzheimer's disease (AD) is characterized by progressive neurodegeneration driven by amyloid-β (Aβ) plaques and tau neurofibrillary tangles. Stress granules (SGs), dynamic ribonucleoprotein condensates formed under cellular stress have been implicated in several neurodegenerative disorders, but their role in AD pathogenesis remains incompletely understood.

METHODS

Following PRISMA-ScR guidelines, we systematically searched PubMed, Embase, Scopus, Web of Science, and Cochrane Library (through February 2026) for peer-reviewed studies investigating SGs in AD models or human tissue. Two reviewers independently screened records, extracted data, and performed narrative synthesis.

RESULTS

Thirty-five studies met inclusion criteria. TIA1 (51.4%) and G3BP1 (42.9%) were the most frequently used SG markers. Multi-model designs incorporating human tissue validation predominated (40.0%). Evidence suggests a bidirectional pathogenic interplay: tau pathology promotes SG assembly and persistence, while SG proteins, particularly TIA1 and USP10 can drive tau oligomerization and toxicity via liquid-liquid phase separation in experimental models. Additional SG network components, including HDAC6 and TRIM21, have been independently implicated in AD pathology, though they remain less explored in direct SG-tau interaction studies. Conversely, G3BP2 exerts protective effects by directly binding tau and inhibiting aggregation. SG dysregulation is associated with disrupted RNA metabolism, sequesteration of AD-associated transcripts, and impaired autophagy. Therapeutic strategies targeting SG modulation, including autophagy enhancers (mTOR inhibitors, myricetin), show promise in reducing tau pathology and SG burden in preclinical systems.

CONCLUSION

The reviewed evidence suggests that SGs are associated with AD pathogenic processes through bidirectional interactions with tau pathology, RNA dysregulation, and proteostatic collapse. These findings, derived largely from preclinical models, support further investigation into SG modulation as a potential therapeutic strategy for AD, while definitive causal roles in human disease remain to be established.