Back to Search
Start Over
Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its pathophysiology.
- Source :
-
Annals of neurology [Ann Neurol] 2015 Aug; Vol. 78 (2), pp. 160-77. Date of Electronic Publication: 2015 Apr 09. - Publication Year :
- 2015
-
Abstract
- 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.<br />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.<br />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.<br />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.<br /> (© 2015 American Neurological Association.)
- Subjects :
- Adult
Aged
Animals
Blood Vessels metabolism
Blood-Brain Barrier metabolism
Brain blood supply
Brain metabolism
Brain pathology
Cerebrovascular Circulation genetics
Disease Models, Animal
Female
Humans
Huntingtin Protein
Huntington Disease genetics
Huntington Disease metabolism
Magnetic Resonance Angiography
Magnetic Resonance Imaging
Male
Mice
Mice, Transgenic
Microscopy, Immunoelectron
Middle Aged
Neostriatum metabolism
Neostriatum pathology
Nerve Tissue Proteins genetics
Nuclear Proteins genetics
Organ Size
Perfusion Imaging
Tight Junction Proteins metabolism
Transcytosis genetics
Blood Vessels pathology
Blood-Brain Barrier pathology
Huntington Disease pathology
Neostriatum blood supply
Nerve Tissue Proteins metabolism
Nuclear Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1531-8249
- Volume :
- 78
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Annals of neurology
- Publication Type :
- Academic Journal
- Accession number :
- 25866151
- Full Text :
- https://doi.org/10.1002/ana.24406