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Cerebrovascular and blood-brain barrier impairments in Huntington's disease: Potential implications for its
Janelle Drouin-Ouellet1, Stephen J Sawiak2, Giulia Cisbani3
1Department of Clinical Neurosciences, John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, United Kingdom.
Insights
Huntington's disease (HD) involves neurovascular unit and blood-brain barrier (BBB) dysfunction. Mutant huntingtin protein aggregates contribute to BBB leakage and vascular changes in both mouse models and HD patients.
Area of Science:
- Neuroscience
- Pathophysiology
- Vascular Biology
Background:
- Huntington's disease (HD) pathophysiology is not fully understood.
- Cerebral vascular and blood-brain barrier (BBB) impairments are implicated in other proteinopathies like Alzheimer's and Parkinson's diseases.
Purpose of the Study:
- To investigate if cerebral vascular and BBB changes are present in Huntington's disease.
- To determine the role of mutant huntingtin protein (mHtt) in these alterations.
Main Methods:
- Utilized 3- and 7-Tesla MRI and postmortem tissue analysis in HD patients.
- Employed in situ cerebral perfusion, histology, Western blotting, and electron microscopy in the R6/2 mouse model.
Main Results:
- Mutant huntingtin protein (mHtt) aggregates found in the neurovascular unit of mice and patients.
- Observed increased blood vessel density, reduced diameter, and BBB leakage in the striatum of R6/2 mice.
- Confirmed similar vascular and BBB changes in HD patients, linked to tight junction protein reduction and transcytotic vesicles.
Conclusions:
- Evidence suggests alterations in cerebral vasculature contribute to BBB leakage in Huntington's disease.
- These vascular changes and BBB leakage may have significant pathophysiological implications for HD progression.
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.
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