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Microglial activation in white matter lesions and nonlesional white matter of ageing brains

Lookup NU author(s): Professor John O'Brien, Dr Robert Barber, Professor Raj Kalaria, Professor Carol Brayne, Professor Pamela Shaw

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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. © 2007 Blackwell Publishing Ltd.


Publication metadata

Author(s): Simpson JE, Ince PG, Higham CE, Gelsthorpe CH, Fernando MS, Matthews F, Forster G, O'Brien JT, Barber R, Kalaria RN, Brayne C, Shaw PJ, Stoeber K, Williams GH, Lewis CE, Wharton SB

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2007

Volume: 33

Issue: 6

Pages: 670-683

Print publication date: 01/12/2007

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/j.1365-2990.2007.00890.x

DOI: 10.1111/j.1365-2990.2007.00890.x

PubMed id: 17990995


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Funding

Funder referenceFunder name
G0400074Medical Research Council
G0502157Medical Research Council
G9901400Medical Research Council
G0300126Medical Research Council
G0500247Medical Research Council
MC_U105292687Medical Research Council

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