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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial activation without peripheral immune cell infiltration characterises mouse and human cerebral small vessel
Tushar Deshpande1, Melanie-Jane Hannocks1, Kishan Kapupara1
1Institute of Physiological Chemistry and Pathobiochemistry and Cells-in-Motion Interfaculty Centre (CiMIC), University of Muenster, Muenster, Germany.
Aims:
Cerebral small vessel diseases (SVDs) involve diverse pathologies of the brain's small blood vessels, leading to cognitive deficits. Cerebral magnetic resonance imaging (MRI) reveals white matter hyperintensities (WMHs), lacunes, microbleeds and enlarged perivascular spaces in SVD patients. Although correlations of MRI and histopathology help to understand the pathogenesis of SVD, they do not explain disease progression. Mouse models, both genetic and sporadic, are valuable for studying SVD, but their resemblance to clinical SVD is unclear. The study examined similarities and differences between mouse models of SVDs and human nonamyloid SVD specimens.
Methods:
We analysed four mouse models of SVD (hypertensive BPH mice, Col4a1 mutants, Notch3 mutants and Htra1-/- mice) at different stages for changes in myelin, blood-brain barrier (BBB) markers, immune cell populations and immune activation. The observations from mouse models were compared with human SVD specimens from different regions, including the periventricular, frontal, central and occipital white matter. Postmortem MRI followed by MBP immunostaining was used to identify white matter lesions (WMLs).
Results:
Only Notch3 mutant and hypertensive BPH mice showed significant changes in myelin basic protein (MBP) immunostaining, correlating with MRI patterns. These changes were linked to altered microglial morphology and focal plasma protein staining around blood vessels, without peripheral immune cell infiltration. In human specimens, both normal-appearing white matter (NAWM) and WMLs lacked peripheral cell infiltration. However, WMLs displayed altered microglial morphology, reduced myelin staining and occasional fibrinogen staining around arterioles and venules.
Conclusions:
Our data show that Notch3 mutants and hypertensive BPH/2J mice recapitulate several features of human SVD, including microglial activation, focal sites of demyelination and perivascular plasma protein leakage without peripheral immune cell infiltration.
Insights
Notch3 mutant and hypertensive mouse models show key features of human small vessel diseases (SVDs), including demyelination and blood-brain barrier leakage. These models mimic SVD pathology without peripheral immune cell involvement, aiding SVD research.
Area of Science:
- Neuroscience
- Pathology
- Medical Imaging
Background:
- Cerebral small vessel diseases (SVDs) are characterized by diverse pathologies affecting the brain's small blood vessels, often leading to cognitive impairment.
- Cerebral MRI reveals markers like white matter hyperintensities (WMHs) and lacunes in SVD patients, but understanding disease progression requires better models.
- Existing mouse models for SVDs vary in their resemblance to human conditions, necessitating comparative studies.
Purpose of the Study:
- To compare similarities and differences between established mouse models of SVDs and human nonamyloid SVD specimens.
- To evaluate the pathological changes in myelin, blood-brain barrier (BBB) integrity, and immune responses within these models and human tissues.
Main Methods:
- Analysis of four SVD mouse models (hypertensive BPH, Col4a1, Notch3, and Htra1-/- mutants) for myelin, BBB markers, and immune cell activity.
- Comparison of mouse model findings with human SVD brain specimens from various white matter regions.
- Utilized postmortem MRI and myelin basic protein (MBP) immunostaining to identify white matter lesions (WMLs).
Main Results:
- Notch3 mutants and hypertensive BPH mice exhibited significant myelin changes (MBP immunostaining) correlating with MRI findings.
- These mice showed altered microglial morphology and focal plasma protein leakage around blood vessels, without peripheral immune cell infiltration.
- Human SVD specimens, both normal-appearing white matter and WMLs, lacked peripheral immune cell infiltration but showed microglial changes, reduced myelin, and occasional fibrinogen staining.
Conclusions:
- Notch3 mutants and hypertensive BPH/2J mice effectively recapitulate key aspects of human SVD.
- These models demonstrate microglial activation, focal demyelination, and perivascular plasma leakage.
- The models' lack of peripheral immune cell infiltration aligns with findings in human SVD tissues, making them valuable for SVD research.
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