Acute amyloid-β exposure disrupts insulin signaling in hCMEC/D3 blood-brain barrier endothelial cells.

Overview

1. Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota,Minneapolis, MN 55455 USA
2. Department of Chemical Engineering and Materials Science, College of Science and Engineering, University of Minnesota,Minneapolis, MN USA
3. Department of Quantitative Health Sciences, Mayo Clinic,Rochester, MN USA

Abstract

Background: Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer’s disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood–brain barrier—a major site of insulin receptor signaling and transport into the brain—remains unclear.

Methods: We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using linear models.

Results: In hCMEC/D3 cells, Aβ40 reduced insulin-stimulated Akt activation and converted insulin’s normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Because the iBMEC model did not show insulin-induced activation of PI3K–Akt signaling, mechanistic interpretation of Aβ effects on insulin-responsive signaling focused on hCMEC/D3 cells.

Conclusions: These findings identify acute Aβ40-sensitive impairment of insulin-responsive Akt signaling in hCMEC/D3 BBB endothelial cells. The results define candidate signaling nodes for further mechanistic study of Aβ effects on BBB insulin-signaling dysfunction.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12987-026-00825-2.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:33413242, at figshare; found in DataCite
• figshare:33413245, at figshare; found in DataCite
• figshare:33413248, at figshare; found in DataCite
• figshare:33413254, at figshare; found in DataCite

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. Processed RPPA expression matrices generated by the MD Anderson Functional Proteomics RPPA Core are included as supplementary files, together with downstream differential expression results for all contrasts.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 7 authors, 7 keywords, 9 MeSH terms, 2 funders, 74 references.

Cite

This paper

Nelson, D. A., Swaminathan, S. K., Veerareddy, V., Seo, H. S., Azarin, S. M., Kalari, K. R., & Kandimalla, K. K. (2026). Acute amyloid-β exposure disrupts insulin signaling in hCMEC/D3 blood-brain barrier endothelial cells. Fluids and barriers of the CNS, 23(1), 106. https://doi.org/10.1186/s12987-026-00825-2

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