ArticleMolecular neurodegeneration2025
Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease.
Article in Molecular neurodegeneration, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- A biomimetic cryoprotectant preserves extracellular vesicles bioactivity for intravenous administration and potentiates wound healing.Journal of nanobiotechnology · 2026Article
- Extracellular vesicle-mediated bidirectional communication between the brain and peripheral organs in Alzheimer's disease: evidence, mechanisms, and translational perspectives.Journal of nanobiotechnology · 2026Review
- Mapping the Ischemic Continuum: Dynamic Multi-Omic Biomarker and AI for Personalized Stroke Care.International journal of molecular sciences · 2026Review
- Blood-brain barrier dysfunction and peripheral immune activation in Alzheimer's disease: an inflammation-centered review.Frontiers in immunology · 2026Review
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Authors and funding
14 authors.
Funding
Abstract
backgroundAlzheimer's disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored.
methodsWe employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice.
resultsThe elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice.
conclusionsThis study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.
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