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<p>Schizophrenia (SZ) is epidemiologically linked to an increased risk of developing age-related dementias (ARD) predominantly characterized by Alzheimer’s disease and vascular dementia. However, the molecular mechanisms underlying this association remain insufficiently elucidated. Extracellular vesicles (EVs) play a critical role in neuropathological processes and offer a promising avenue for identifying shared disease mechanisms and potential circulating markers for patient stratification. Here we used a two-phase systems biology approach integrating discovery-driven proteomics with a targeted validation strategy using data-independent acquisition mass spectrometry (DIA-MS) in a large, independent SZ cohort. First, we analyzed brain-derived EVs (bEVs) from post-mortem SZ and ARD subjects to identify shared molecular signatures. Next, we validated the presence and circulation of these bEV markers in circulating plasma EVs (pEVs) using DIA-MS data. Remarkably, SZ and ARD bEV proteome and peptidome showed overlapping alterations in neuronal connectivity, synaptic integrity, neuroinflammation, and metabolism. Unsupervised clustering analysis of correlated bEV/pEV markers stratified SZ patients into two clusters: high dementia risk and control-like profiles. Collectively, these data emphasize the significance of bEVs as crucial mediators of shared neuropathogenic mechanisms in SZ, and ARD. Furthermore, we identified a set of pEVs markers, including proteins and specific peptides, with a robust and promising bench-to-bedside trajectory that may facilitate the stratification of SZ patients at risk for ARD.</p>

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Brain and circulating EV proteome signatures in schizophrenia as prognostic markers for age-related dementia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月20日

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  • Jose Antonio Sánchez Milán,
  • Maria Mulet,
  • Itziar Molet,
  • Julia Lisa-Molina,
  • Maria Font-Alberich,
  • Cristina Lorca,
  • Montserrat Gea-Sánchez,
  • Filip Bellon,
  • Iolanda Batalla,
  • J Javier Meana,
  • Luis F Callado,
  • Benito Morentin,
  • Alfredo Ramos-Miguel,
  • Raj N Kalaria,
  • Aida Serra,
  • Xavier Gallart-Palau

摘要

Schizophrenia (SZ) is epidemiologically linked to an increased risk of developing age-related dementias (ARD) predominantly characterized by Alzheimer’s disease and vascular dementia. However, the molecular mechanisms underlying this association remain insufficiently elucidated. Extracellular vesicles (EVs) play a critical role in neuropathological processes and offer a promising avenue for identifying shared disease mechanisms and potential circulating markers for patient stratification. Here we used a two-phase systems biology approach integrating discovery-driven proteomics with a targeted validation strategy using data-independent acquisition mass spectrometry (DIA-MS) in a large, independent SZ cohort. First, we analyzed brain-derived EVs (bEVs) from post-mortem SZ and ARD subjects to identify shared molecular signatures. Next, we validated the presence and circulation of these bEV markers in circulating plasma EVs (pEVs) using DIA-MS data. Remarkably, SZ and ARD bEV proteome and peptidome showed overlapping alterations in neuronal connectivity, synaptic integrity, neuroinflammation, and metabolism. Unsupervised clustering analysis of correlated bEV/pEV markers stratified SZ patients into two clusters: high dementia risk and control-like profiles. Collectively, these data emphasize the significance of bEVs as crucial mediators of shared neuropathogenic mechanisms in SZ, and ARD. Furthermore, we identified a set of pEVs markers, including proteins and specific peptides, with a robust and promising bench-to-bedside trajectory that may facilitate the stratification of SZ patients at risk for ARD.