Stress granule and Tau oligomer interplay reveals subtype-specific functional aggregation signatures in Alzheimer’s disease

Introduction:
Alzheimer’s disease (AD) includes clinically heterogeneous subtypes, such as slowly progressive AD (spAD) and rapidly progressive AD (rpAD). Understanding molecular distinctions between these forms may reveal mechanisms that drive disease severity and progression.

Objectives:
We aimed to characterize tau oligomers (TauO) and stress granules (SGs) in spAD and rpAD and to investigate their potential molecular interplay.

Methods:
SGs were isolated from human frontal cortex and analyzed using biochemical fractionation, immunoprecipitation, and mass spectrometry. Transmission electron microscopy (TEM) was used to examine SG morphology, while SG-associated RNAs were profiled via RNA sequencing. TauO were assessed by TEM, Western blotting for post-translational modifications (PTMs), and neuronal cell-based toxicity assays. Overlapping proteins between SGs and TauO were identified through interactome analysis.

Results/Discussion:
SGs in rpAD displayed altered morphology and compositional shifts in proteins related to RNA regulation, cytoskeletal structure, and translation machinery RNA-seq revealed depletion of transcripts essential for synaptic maintenance and translation. TauO in rpAD showed phosphorylation at S396 and S422 and induced reduced viability in neuronal models. Notably, proteomic overlap between SGs and TauO revealed subtype-specific functional aggregation signatures, reflecting coordinated disruption of RNA processing, translation control, and protein homeostasis. Given that both SGs and TauO are implicated in pathological aggregation, their molecular convergence may contribute to disease-specific protein dysfunction in rpAD.

Conclusion:
These findings reveal distinct molecular features of SGs and TauO in AD, suggesting their combined role in disrupting protein-RNA regulatory networks associated with disease progression.