Cerebrovascular and blood–brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology
Janelle Drouin-Ouellet PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorStephen J. Sawiak PhD
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorGiulia Cisbani PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorMarie Lagacé MSc
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorWei-Li Kuan PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorMartine Saint-Pierre DEC
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorRichard J. Dury MSc
Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
Search for more papers by this authorWael Alata MSc
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorIsabelle St-Amour PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorSarah L. Mason PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorFrédéric Calon PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Faculté de Pharmacie, Université Laval, Québec, Québec, Canada
Search for more papers by this authorSteve Lacroix PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Département de Médecine Moléculaire, Université Laval, Québec, Québec, Canada
Search for more papers by this authorPenny A. Gowland PhD
Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
Search for more papers by this authorSusan T. Francis PhD
Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
Search for more papers by this authorRoger A. Barker MD, PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorCorresponding Author
Francesca Cicchetti PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Département de Psychiatrie & Neurosciences, Université Laval, Québec, Québec, Canada
Address correspondence to Dr. Francesca Cicchetti, Centre de recherche du CHU de Québec, Axe Neurosciences, T2–50, 2705, Boulevard Laurier, Québec, QC, Canada G1V 4G2. E-mail: [email protected]Search for more papers by this authorJanelle Drouin-Ouellet PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorStephen J. Sawiak PhD
Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorGiulia Cisbani PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorMarie Lagacé MSc
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorWei-Li Kuan PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorMartine Saint-Pierre DEC
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorRichard J. Dury MSc
Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
Search for more papers by this authorWael Alata MSc
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorIsabelle St-Amour PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Search for more papers by this authorSarah L. Mason PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorFrédéric Calon PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Faculté de Pharmacie, Université Laval, Québec, Québec, Canada
Search for more papers by this authorSteve Lacroix PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Département de Médecine Moléculaire, Université Laval, Québec, Québec, Canada
Search for more papers by this authorPenny A. Gowland PhD
Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
Search for more papers by this authorSusan T. Francis PhD
Sir Peter Mansfield Magnetic Resonance Centre, School of Physics and Astronomy, University of Nottingham, Nottingham, United Kingdom
Search for more papers by this authorRoger A. Barker MD, PhD
Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom
Search for more papers by this authorCorresponding Author
Francesca Cicchetti PhD
Centre de recherche du CHU de Québec (CHUQ), Québec, Québec, Canada
Département de Psychiatrie & Neurosciences, Université Laval, Québec, Québec, Canada
Address correspondence to Dr. Francesca Cicchetti, Centre de recherche du CHU de Québec, Axe Neurosciences, T2–50, 2705, Boulevard Laurier, Québec, QC, Canada G1V 4G2. E-mail: [email protected]Search for more papers by this authorAbstract
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. Ann Neurol 2015;78:160–177
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