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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate
Xiaoyang Lu1, Yiling Jiang1, Xiuqing Lin1
1State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, East China University of Science and Technology, Shanghai, 200237, China.
Background:
Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.
Results:
In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function.
Conclusions:
By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.