Angiopoietin signalling is a central axis of amyloid-driven vascular dysfunction in Alzheimer's disease

Flotho, M.; Yang, A.; Kern, F.; Graf, S.; Diks, I. F.; Shin, H.; Berdnik, D.; Agam, M.; Channappa, D.; Shi, S.; Belnap, M. A.; Simmons, E.; Bradshaw, K.; Grandke, F.; Bennett, D. A.; Buckwalter, M.; Keller, A.; Wyss-Coray, T.

doi:10.1101/2025.08.25.672093

bioRxiv · 10.1101/2025.08.25.672093

Angiopoietin signalling is a central axis of amyloid-driven vascular dysfunction in Alzheimer's disease

Flotho, M.·Yang, A.·Kern, F.·Graf, S.·Diks, I. F.·Shin, H.·Berdnik, D.·Agam, M.·Channappa, D.·Shi, S.·Belnap, M. A.·Simmons, E.·Bradshaw, K.·Grandke, F.·Bennett, D. A.·Buckwalter, M.·Keller, A.·Wyss-Coray, T.

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Abstract

The neurovascular unit is critical for brain health, and its dysfunction has been linked to Alzheimers disease (AD). However, a cell-type-resolved understanding of how diverse vascular cells become dysfunctional and contribute to disease has been missing. Here, we applied Vessel Isolation and Nuclei Extraction for Sequencing (VINE-seq) to build a comprehensive transcriptomic atlas from 101 individuals along AD progression. Our analysis of over 842,646 parenchymal and vascular nuclei reveals that vascular dysfunction in AD is driven by transcriptional changes rather than shifts in cell proportions, with brain endothelial cells (BECs) and smooth muscle cells (SMCs) most affected. Strikingly, these molecular signatures emerge early at the mild cognitive impairment (MCI) stage, implicating vascular dysfunction early in AD pathogenesis. Stratifying by pathology reveals distinct vascular responses to {beta}-amyloid and tau: {beta}-amyloid burden primarily perturbs BECs and SMCs, while tau pathology predominantly impacts glial cells. We identify dysregulated angiopoietin signaling across multiple vascular cell types as a key axis, with antagonistic ANGPT2 in vascular cells and ANGPT1 in astrocytes becoming progressively dysregulated with AD. Together, this work provides a foundational resource that reveals early and pathology-specific pathways of vascular dysfunction in AD. Key MessagesO_LIVINE-seq analysis from 101 individuals creates a comprehensive human brain vascular atlas across Alzheimers disease (AD) progression. C_LIO_LIAD vascular dysfunction is driven by transcriptional changes rather than shifts in cell proportions, with BECs and SMCs most affected. C_LIO_LITranscriptional signatures of vascular dysfunction emerge early at the mild cognitive impairment (MCI) stage, preceding severe cognitive symptoms and aligning more closely with AD than cognitively normal individuals. C_LIO_LIA{beta} and tau associate with distinct vascular changes: A{beta} mainly perturbs endothelial and smooth muscle cells, while tau impacts microglia and astrocytes. C_LIO_LIAngiopoietin signaling (antagonistic ANGPT2 in vascular cells vs. ANGPT1 in astrocytes) becomes progressively dysregulated during AD progression. C_LI

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Flotho, M., Yang, A., Kern, F., Graf, S., Diks, I. F., Shin, H., Berdnik, D., Agam, M., Channappa, D., Shi, S., Belnap, M. A., Simmons, E., Bradshaw, K., Grandke, F., Bennett, D. A., Buckwalter, M., Keller, A., Wyss-Coray, T.. 2025-08-29. Angiopoietin signalling is a central axis of amyloid-driven vascular dysfunction in Alzheimer's disease. https://doi.org/10.1101/2025.08.25.672093

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