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bioRxiv · 10.1101/2025.05.23.655679

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

Kumar, S.·Zehra, S.·Rai, S.·Rani, K.·Choudhury, S. D.·Rai, H.·Bhowmik, S.·Mohan, N.·Gupta, A.·Chatterjee, P.·Reddy, T. J.·Rani, N.·Modi, G. P.·Nikolajeff, F.
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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

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Kumar, S., Zehra, S., Rai, S., Rani, K., Choudhury, S. D., Rai, H., Bhowmik, S., Mohan, N., Gupta, A., Chatterjee, P., Reddy, T. J., Rani, N., Modi, G. P., Nikolajeff, F.. 2025-05-27. Stress-Induced Alteration of Small Extracellular Vesicles Drives Amyloid-Beta Sequestration and Exacerbates Alzheimer's Disease Pathogenesis. https://doi.org/10.1101/2025.05.23.655679

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