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Microglia in neurodegenerative disease

Abstract

Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.

Key Points

  • The phenotype of microglia is tightly regulated within the normal healthy CNS

  • Microglia rapidly change their morphology and expression of diverse molecules in response to changes in homeostasis and pathological insults to the brain

  • Morphologically activated microglia display diverse phenotypes that critically depend on the sequence and duration of their exposure to various stimuli in different pathologies

  • Microglial morphology and changes in expression of a small number of markers are not simple guides to microglial phenotype and function

  • Microglial phenotype is modified by systemic infection and inflammation

  • Systemic inflammation influences the symptoms and progression of chronic neurodegenerative disease

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Figure 1: Diffuse distribution of activated microglia in the cerebral cortex of a patient with Creutzfeldt–Jakob disease.
Figure 2: Aβ immunization in Alzheimer disease induces amyloid plaque phagocytosis by activated microglia.
Figure 3: Microglial phenotypes.

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Acknowledgements

Work in the authors' laboratories is supported by the Medical Research Council, the Alzheimer's Research Trust, the Alzheimer's Society, and the Wellcome Trust. We are grateful to Prof. Peter Beverley for discussions on innate immune memory.

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Perry, V., Nicoll, J. & Holmes, C. Microglia in neurodegenerative disease. Nat Rev Neurol 6, 193–201 (2010). https://doi.org/10.1038/nrneurol.2010.17

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