Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology.

Janelle Drouin‐Ouellet,Steve Lacroix,Stephen J Sawiak,Susan T Francis,Francesca Cicchetti,Martine Saint‐Pierre,Penny A Gowland,Sarah L Mason,Giulia Cisbani,Isabelle St‐Amour,Roger A Barker,Wei‐Li Kuan,Richard J Dury,Marie Lagacé,Frédéric Calon,Wael Alata

doi:10.1002/ana.24406

Abstract

Although the underlying cause of Huntington's disease (HD) is well established, the actual pathophysiological processes involved remain to be fully elucidated. In other proteinopathies such as Alzheimer's and Parkinson's diseases, there is evidence for impairments of the cerebral vasculature as well as the blood-brain barrier (BBB), which have been suggested to contribute to their pathophysiology. We investigated whether similar changes are also present in HD. We used 3- and 7-Tesla magnetic resonance imaging as well as postmortem tissue analyses to assess blood vessel impairments in HD patients. Our findings were further investigated in the R6/2 mouse model using in situ cerebral perfusion, histological analysis, Western blotting, as well as transmission and scanning electron microscopy. We found mutant huntingtin protein (mHtt) aggregates to be present in all major components of the neurovascular unit of both R6/2 mice and HD patients. This was accompanied by an increase in blood vessel density, a reduction in blood vessel diameter, as well as BBB leakage in the striatum of R6/2 mice, which correlated with a reduced expression of tight junction-associated proteins and increased numbers of transcytotic vesicles, which occasionally contained mHtt aggregates. We confirmed the existence of similar vascular and BBB changes in HD patients. Taken together, our results provide evidence for alterations in the cerebral vasculature in HD leading to BBB leakage, both in the R6/2 mouse model and in HD patients, a phenomenon that may, in turn, have important pathophysiological implications.

Highlights

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a range of motor, cognitive, psychiatric and metabolic abnormalities
Expression of mutant huntingtin (mHtt) pathology in cerebral blood vessels Building on our previous observation that mHtt aggregates were found in the basal membrane of cerebral blood vessels of HD patients 10, we first assessed the expression of mHtt aggregates in all compartments of the neurovascular unit. mHtt aggregates were observed inside the basal membrane sheaths as well as in the nuclei of cells embedded in the basal membrane in both small- (5-10 μm) and large-calibre (>20 μm) blood vessels (Fig. 1A to C). mHtt aggregates were found to colocalize with vWF-labelled endothelial cells (Fig. 1D to G), as well as -SMA+ cells within the basal membrane (Fig. 1H) and CD163+ perivascular macrophages (Fig. 1I)
Vascular changes in the putamen of HD patients Given that mHtt can impair mitochondrial integrity and elicit oxidative stress, which may affect the physiology of cells composing the cerebral vasculature [37,38], we investigated morphological, structural and functional changes in blood vessels in the context of HD using MRI and post-mortem HD tissue

Summary

Introduction

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that presents with a range of motor, cognitive, psychiatric and metabolic abnormalities. Our recent post-mortem analysis of HD patients who had been in receipt of fetal striatal allografts has revealed the presence of mHtt aggregates within the genetically-unrelated grafted tissue 10 These mHtt aggregates were found almost exclusively within the extracellular matrix of the grafted tissue, and in cells associated with blood vessels as well as within perivascular macrophages 10. This provided the first in vivo demonstration of mHtt spread in patients with a monogenic human neurodegenerative disorder of the central nervous system (CNS), and suggested the existence of non cell-autonomous mechanisms of pathological protein transmission. Despite the fact that the latter cells have limited access to the CNS due to the bloodbrain-barrier (BBB), there is increasing evidence that a number of neurodegenerative disorders are associated with alterations in the cerebrovasculature, including the neurovascular unit and the BBB 12,13, which may facilitate the access of peripheral cells to the CNS compartment

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