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Background <p>With the progression of late-onset Alzheimer disease (LOAD), there is a dysregulation and then a breakdown of the blood-brain barrier (BBB). An important pathological feature in the brains of patients is the accumulation of amyloid beta (Aβ) peptides. Their aggregation leads to the formation of particularly harmful Aβ oligomers (Aβ-O). Unfortunately, our understanding of changes in the blood-brain barrier, particularly with regard to the effects of Aβ-O, is still very limited.</p> Methods <p>This study investigated a LOAD-specific and induced pluripotent stem cell (hiPSC)-based in vitro model of the BBB for disease mechanisms and validated the findings in two independent laboratories. This study also investigated Aβ transport across the BBB. Furthermore, obtained in vitro findings were confirmed in the cerebrospinal fluid proteome of a LOAD patient cohort.</p> Results <p>Control and LOAD hiPSCs exhibited comparable efficiency in forming brain capillary endothelial-like cells (BCECs). Although transendothelial electrical resistance (TEER) assessments indicated no significant differences in barrier tightness between LOAD and control BCECs, high-throughput multiplex qPCR analysis revealed subtle alterations in barrier integrity. This included changes in various barrier markers, such as mucins (MUC1, MUC20), aquaporins (AQP5, AQP10), junctional transcripts (CLDNs, TJP1, OCLN), and receptors (LRP1, INSR, LSR), which were confirmed in LOAD patients. High-content imaging and flow cytometry indicated reduced cadherin 5 (CDH5) levels in LOAD BCECs. Importantly, the results also highlighted a difference in the transport of Aβ-O across the BBB.</p> Conclusion <p>This model demonstrates a LOAD-relevant phenotype with decreased Aβ transport and alterations in key transcripts and could thus serve for future translational studies to rescue pathogenic phenotypes.</p> Graphical Abstract <p></p>

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Brain capillary endothelial-like cells show altered barrier functionality and reduced transport of amyloid β in late-onset Alzheimer disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月22日

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  • Carla Hartmann,
  • Undine Haferkamp,
  • Antje Appelt-Menzel,
  • Janica Barenberg,
  • Andreas Brachner,
  • Toni Ehrhard,
  • Julia Feldhaus,
  • Anna Gerhartl,
  • Thomas Hollemann,
  • Linda Anna Michelle Kulka,
  • Selin Leckzik,
  • Jennifer Leu,
  • Marcel Seungsu Woo,
  • Manuel Alexander Friese,
  • Alzheimer’s Disease Neuroimaging Initiative,
  • Marco Metzger,
  • Winfried Neuhaus,
  • Sabrina Oerter,
  • Heidi Olzscha,
  • Andreas Pich,
  • Dagmar Riemann,
  • Ole Pless,
  • Dan Rujescu,
  • Matthias Jung

摘要

Background

With the progression of late-onset Alzheimer disease (LOAD), there is a dysregulation and then a breakdown of the blood-brain barrier (BBB). An important pathological feature in the brains of patients is the accumulation of amyloid beta (Aβ) peptides. Their aggregation leads to the formation of particularly harmful Aβ oligomers (Aβ-O). Unfortunately, our understanding of changes in the blood-brain barrier, particularly with regard to the effects of Aβ-O, is still very limited.

Methods

This study investigated a LOAD-specific and induced pluripotent stem cell (hiPSC)-based in vitro model of the BBB for disease mechanisms and validated the findings in two independent laboratories. This study also investigated Aβ transport across the BBB. Furthermore, obtained in vitro findings were confirmed in the cerebrospinal fluid proteome of a LOAD patient cohort.

Results

Control and LOAD hiPSCs exhibited comparable efficiency in forming brain capillary endothelial-like cells (BCECs). Although transendothelial electrical resistance (TEER) assessments indicated no significant differences in barrier tightness between LOAD and control BCECs, high-throughput multiplex qPCR analysis revealed subtle alterations in barrier integrity. This included changes in various barrier markers, such as mucins (MUC1, MUC20), aquaporins (AQP5, AQP10), junctional transcripts (CLDNs, TJP1, OCLN), and receptors (LRP1, INSR, LSR), which were confirmed in LOAD patients. High-content imaging and flow cytometry indicated reduced cadherin 5 (CDH5) levels in LOAD BCECs. Importantly, the results also highlighted a difference in the transport of Aβ-O across the BBB.

Conclusion

This model demonstrates a LOAD-relevant phenotype with decreased Aβ transport and alterations in key transcripts and could thus serve for future translational studies to rescue pathogenic phenotypes.

Graphical Abstract