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

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Cerebrovascular and blood-brain barrier impairments in Huntington's disease : Potential implications for its pathophysiology. / Drouin-Ouellet, Janelle; Sawiak, Stephen J; Cisbani, Giulia; Lagacé, Marie; Kuan, Wei-Li; Saint-Pierre, Martine; Dury, Richard J; Alata, Wael; St-Amour, Isabelle; Mason, Sarah L; Calon, Frédéric; Lacroix, Steve; Gowland, Penny A; Francis, Susan T; Barker, Roger A; Cicchetti, Francesca.

I: Annals of Neurology, Vol. 78, Nr. 2, 08.2015, s. 160-77.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

Drouin-Ouellet, J, Sawiak, SJ, Cisbani, G, Lagacé, M, Kuan, W-L, Saint-Pierre, M, Dury, RJ, Alata, W, St-Amour, I, Mason, SL, Calon, F, Lacroix, S, Gowland, PA, Francis, ST, Barker, RA & Cicchetti, F 2015, 'Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology', Annals of Neurology, vol. 78, nr. 2, s. 160-77. https://doi.org/10.1002/ana.24406

APA

Drouin-Ouellet, J., Sawiak, S. J., Cisbani, G., Lagacé, M., Kuan, W-L., Saint-Pierre, M., ... Cicchetti, F. (2015). Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology. Annals of Neurology, 78(2), 160-77. https://doi.org/10.1002/ana.24406

CBE

Drouin-Ouellet J, Sawiak SJ, Cisbani G, Lagacé M, Kuan W-L, Saint-Pierre M, Dury RJ, Alata W, St-Amour I, Mason SL, Calon F, Lacroix S, Gowland PA, Francis ST, Barker RA, Cicchetti F. 2015. Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology. Annals of Neurology. 78(2):160-77. https://doi.org/10.1002/ana.24406

MLA

Vancouver

Author

Drouin-Ouellet, Janelle ; Sawiak, Stephen J ; Cisbani, Giulia ; Lagacé, Marie ; Kuan, Wei-Li ; Saint-Pierre, Martine ; Dury, Richard J ; Alata, Wael ; St-Amour, Isabelle ; Mason, Sarah L ; Calon, Frédéric ; Lacroix, Steve ; Gowland, Penny A ; Francis, Susan T ; Barker, Roger A ; Cicchetti, Francesca. / Cerebrovascular and blood-brain barrier impairments in Huntington's disease : Potential implications for its pathophysiology. I: Annals of Neurology. 2015 ; Vol. 78, Nr. 2. s. 160-77.

RIS

TY - JOUR

T1 - Cerebrovascular and blood-brain barrier impairments in Huntington's disease

T2 - Annals of Neurology

AU - Drouin-Ouellet, Janelle

AU - Sawiak, Stephen J

AU - Cisbani, Giulia

AU - Lagacé, Marie

AU - Kuan, Wei-Li

AU - Saint-Pierre, Martine

AU - Dury, Richard J

AU - Alata, Wael

AU - St-Amour, Isabelle

AU - Mason, Sarah L

AU - Calon, Frédéric

AU - Lacroix, Steve

AU - Gowland, Penny A

AU - Francis, Susan T

AU - Barker, Roger A

AU - Cicchetti, Francesca

N1 - © 2015 American Neurological Association.

PY - 2015/8

Y1 - 2015/8

N2 - OBJECTIVE: 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.METHODS: 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.RESULTS: 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.INTERPRETATION: 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.

AB - OBJECTIVE: 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.METHODS: 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.RESULTS: 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.INTERPRETATION: 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.

KW - Adult

KW - Aged

KW - Animals

KW - Blood Vessels

KW - Blood-Brain Barrier

KW - Brain

KW - Cerebrovascular Circulation

KW - Disease Models, Animal

KW - Female

KW - Humans

KW - Huntington Disease

KW - Magnetic Resonance Angiography

KW - Magnetic Resonance Imaging

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Microscopy, Immunoelectron

KW - Middle Aged

KW - Neostriatum

KW - Nerve Tissue Proteins

KW - Nuclear Proteins

KW - Organ Size

KW - Perfusion Imaging

KW - Tight Junction Proteins

KW - Transcytosis

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1002/ana.24406

DO - 10.1002/ana.24406

M3 - Article

VL - 78

SP - 160

EP - 177

JO - Annals of Neurology

JF - Annals of Neurology

SN - 1531-8249

IS - 2

ER -