Stress-Induced Alteration of Small Extracellular Vesicles Drives Amyloid-Beta Sequestration and Exacerbates Alzheimer's Disease Pathogenesis

Abstract

While small extracellular vesicles (sEVs) are implicated in amyloid-beta (A{beta}) trafficking, the mechanisms governing their interaction with A{beta} aggregates and plaque formation remain unresolved. Here, we report a paradigm-shifting discovery: sEVs undergo dynamic structural remodelling in response to stress, enabling selective binding to A{beta} aggregates-a phenomenon absent under normal physiological conditions. Using multimodal stressors, including mechanical (ultrasonication/agitation), physical (hyperthermia), and biological (oxidative damage), we demonstrate that stress-modified sEVs exhibit high-affinity binding to small A{beta} aggregates (SA) through scaffold reorganization, as validated by super-resolution microscopy and quantitative colocalization assays. Crucially, these remodelled sEVs act as potent carriers, enhancing SA internalization by neuronal cells in vitro. Strikingly, in post-mortem Alzheimers disease (AD) brains and APP-PS1 transgenic mice, sEVs were spatially enriched at amyloid plaque margins, suggesting a direct role in A{beta} sequestration and plaque expansion. Consistent with clinical relevance, sEVs isolated from AD patients exhibited an intrinsic SA-binding capacity, recapitulating stress-induced interactions observed experimentally. Our findings reveal that stress-primed sEVs function as pathological chaperones, binding to and internalizing A{beta} aggregates, thereby accelerating plaque nucleation and disease progression. This study provides the first evidence of stress-mediated sEV plasticity as a critical driver of A{beta} pathology, redefining therapeutic strategies targeting extracellular vesicle biology in neurodegenerative disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/655679v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@107c76borg.highwire.dtl.DTLVardef@1b56848org.highwire.dtl.DTLVardef@d18636org.highwire.dtl.DTLVardef@1c26db4_HPS_FORMAT_FIGEXP M_FIG C_FIG