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PSEN1 ΔE9 NPC-derived extracellular vesicles modulate neural and metabolic gene programs in brain organoids
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DOI：10.1186/s40478-026-02401-z.png)
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Abstract
En 中文
Extracellular vesicles (EVs) are increasingly recognized as key mediators of intercellular communication in neurodegenerative disorders, yet their mechanistic contribution to Alzheimer’s disease (AD)-related molecular changes remains poorly understood. Neural progenitor cells (NPCs) are particularly relevant because deficits in their proliferation and differentiation impair neurogenesis and brain repair. To investigate how EVs may influence these processes, we isolated EVs through size exclusion chromatography (SEC) from induced pluripotent stem cells (iPSCs)- derived NPCs carrying the AD-associated PSEN1 ΔE9 mutation and from isogenic controls. EV formulations were characterized by nanoparticle tracking analysis, cryogenic transmission electron microscopy, immunoblotting, and liquid chromatography–tandem mass spectrometry-based proteomics. Their effects on iPSC-derived brain organoids (BOs) were assessed by transcriptomic profiling. AD NPC EVs showed increased 6E10-reactive Aβ-related signal and contained AD-associated protein signatures, including PZP, ALPL, POSTN, APOC3, and transferrin. Application of AD EV preparations to healthy BOs induced transcriptomic changes that partially overlapped with AD BO transcriptomic signatures, including altered developmental and synapse-associated gene programs and downregulation of metabolic pathways. Consistently, PSEN1 ΔE9 NPCs showed reduced oxidative phosphorylation and glycolysis in Seahorse extracellular flux assays, while PSEN1 ΔE9 EV-treated BOs displayed downregulation of TCA cycle and glycolytic pathways at the transcriptomic level. Together, our findings suggest that NPC-derived SEC-enriched EV preparations contain AD-associated molecular signatures that could affect developmental, synapse-associated, and metabolic gene programs in recipient BOs, providing insight into cell-cell communication in AD.
Keywords:
Alzheimer’s disease
Extracellular vesicles
iPSC technology
Proteomics
Transcriptomics
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