Microglial activation in white matter lesions and nonlesional white matter of ageing brains
J E Simpson1, P G Ince, C E Higham
1Academic Unit of Pathology, University of Sheffield Medical School, Sheffield, UK.
Abstract:
White matter lesions (WML), a common feature in brain ageing, are classified as periventricular (PVL) or deep subcortical (DSCL), depending on their anatomical location. Microglial activation is implicated in a number of neurodegenerative diseases, but the microglial response in WML is poorly characterized and its role in pathogenesis unknown. We have characterized the microglial response in WML and control white matter using immunohistochemistry to markers of microglial activation and of proliferation. WML of brains from an unbiased population-based autopsy cohort (Medical Research Council's Cognitive Function and Ageing Study) were identified by post mortem magnetic resonance imaging and sampled for histology. PVL contain significantly more activated microglia, expressing major histocompatibility complex (MHC) class II and the costimulatory molecules B7-2 and CD40, than either control white matter (WM) or DSCL. Furthermore, we show that significantly more microglia express the replication licensing protein minichromosome maintenance protein 2 within PVL, suggesting this is a more proliferation-permissive environment than DSCL. Although microglial activation occurs in both PVL and DSCL, our findings suggest a difference in pathogenesis between these lesion-types: the ramified, activated microglia associated with PVL may reflect immune activation resulting from disruption of the blood brain barrier, while the microglia within DSCL may reflect an innate, amoeboid phagocytic phenotype. We also show that microglia in control WM from lesional cases express significantly more MHC II than control WM from nonlesional ageing brain, suggesting that WML occur in a 'field-effect' of abnormal WM.
Insights
Periventricular white matter lesions (PVL) show increased microglial activation and proliferation compared to deep subcortical lesions (DSCL). This suggests distinct pathogenic mechanisms for different white matter lesion types in aging brains.
Area of Science:
- Neuroscience
- Immunology
- Neuropathology
Background:
- White matter lesions (WML) are common in brain aging and classified as periventricular (PVL) or deep subcortical (DSCL).
- Microglial activation is linked to neurodegeneration, but its role in WML pathogenesis is unclear.
- The specific microglial response within different WML types requires detailed characterization.
Purpose of the Study:
- To characterize the microglial response, including activation and proliferation, in PVL and DSCL.
- To investigate potential differences in the pathogenesis of PVL versus DSCL.
- To explore the concept of a 'field-effect' in the development of WML.
Main Methods:
- Utilized immunohistochemistry to analyze microglial markers of activation and proliferation.
- Examined brain tissue from an unbiased autopsy cohort (Medical Research Council's Cognitive Function and Ageing Study).
- Identified WML using post-mortem magnetic resonance imaging before histological sampling.
Main Results:
- PVL exhibited significantly higher levels of activated microglia (expressing MHC class II, B7-2, CD40) than control white matter or DSCL.
- PVL showed increased microglial proliferation, indicated by minichromosome maintenance protein 2 expression, suggesting a more permissive environment.
- Microglia in control white matter from individuals with lesions expressed more MHC II than those from non-lesional brains, supporting a 'field-effect'.
Conclusions:
- Microglial activation differs between PVL and DSCL, suggesting distinct pathogenic pathways.
- PVL microglia may reflect blood-brain barrier disruption and immune activation, while DSCL microglia exhibit an innate phagocytic phenotype.
- WML development might involve a broader 'field-effect' ofWM abnormalities beyond the visible lesions.
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