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

ABSTRACT: 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 by paracellular leakage, while the blood-brain barrier (BBB) of parenchymal vessels exhibited increased vesicular transport and adsorptive-mediated transcytosis (AMT), with arterioles representing the most critically impacted vascular segment. The pathology of both barriers was congruent with astrocyte activation localized to affected vessels in R6/2 mice, as well as in post-mortem HD human brains. Sphingosine-1-phosphate receptor 1 (S1pr1) agonist treatment reversed BCSFB leakage but only 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.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Plasma, Cerebrospinal Fluid

DISEASE(S): Huntington Disease

SUBMITTER: Niels Henning Skotte  

LAB HEAD: Niels Skotte

PROVIDER: PXD081397 | Pride | 2026-08-14

REPOSITORIES: Pride