Huntington’s disease vasculopathy is barrier-type-selective and arteriolar-dominant with spatially-coupled astrogliosis and reversible by S1pr1 stimulation

Brain vascular barriers are dysfunctional in many neurological disorders, including Huntington’s disease (HD), but which vessels are affected and how remains unclear. Using in vivo two-photon microscopy in R6/2 HD-model mice, we reveal a striking divergence in barrier dysfunction. Surface vessels of the blood-cerebrospinal fluid barrier (BCSFB) drive pathology in HD by paracellular leakage, while parenchymal vessels forming the blood-brain barrier (BBB) exhibit increased vesicular transport and adsorptive-mediated transcytosis (AMT), with arterioles representing the most critically impacted vascular segment.

The pathology of both barriers was spatially-matched with astrocyte activation pattern localized to affected vessels both in R6/2 mice and in brains of HD patients. Sphingosine-1-phosphate receptor 1 (S1pr1) agonist treatment reversed BCSFB leakage and partially restored BBB function, selectively reducing AMT in arterioles, with no effect in capillaries and venules. These findings redefine HD vascular pathology, demonstrating heterogeneous, vessel-type-specific barrier failure beyond generalized “disruption,” uncovering mechanistic vulnerabilities and the therapeutic potential of S1pr1 modulation.

Micael Lønstrup for his excellent assistance with animal surgeries and Kjeld Møllgård for his insightful comments on the manuscript. This study was supported by the Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis’ Legat, Lundbeck Foundation (#R392-2018-2266 and #R345-2020-1440), the Danish Medical Research Council (#1030-00374 A), the Independent Research Fund Denmark, and the Novo Nordisk Foundation (#117272 and NNF14CC0001). RSK receives funding from the Swedish Research Council (#2023-02939) and Åke Wibergs Foundation (#M22-0192).

F.C. receives funding from the Canadian Institutes of Health Research (CIHR, PJT162164 and PJT168865) to conduct HD-related work. Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark Krzysztof Kucharz, Rana Soylu-Kucharz & Martin Johannes Lauritzen Department of Experimental Medical Science, Lund University, Lund, Sweden Centre de Recherche du CHU de Québec, Axe Neurosciences, Québec City, QC, Canada Martine Saint-Pierre & Francesca Cicchetti Département de Psychiatrie & Neurosciences, Université Laval, Québec City, QC, Canada Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark Filippa Liliendahl Qvist & Niels Henning Skotte NNF Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Kucharz, K., Soylu-Kucharz, R., Saint-Pierre, M. et al. Huntington’s disease vasculopathy is barrier-type-selective and arteriolar-dominant with spatially-coupled astrogliosis and reversible by S1pr1 stimulation.