Microglia are involved in the communication of systemic inflammation to the brain
Microglia become primed by systemic inflammation or neurodegeneration
The exaggerated response of primed microglia to systemic inflammation contributes to the pathogenesis of neurodegenerative disease
Modulation of systemic inflammation offers novel strategies in the prevention and therapy of neurodegenerative disease
Under physiological conditions, the number and function of microglia—the resident macrophages of the CNS—is tightly controlled by the local microenvironment. In response to neurodegeneration and the accumulation of abnormally folded proteins, however, microglia multiply and adopt an activated state—a process referred to as priming. Studies using preclinical animal models have shown that priming of microglia is driven by changes in their microenvironment and the release of molecules that drive their proliferation. Priming makes the microglia susceptible to a secondary inflammatory stimulus, which can then trigger an exaggerated inflammatory response. The secondary stimulus can arise within the CNS, but in elderly individuals, the secondary stimulus most commonly arises from a systemic disease with an inflammatory component. The concept of microglial priming, and the subsequent exaggerated response of these cells to secondary systemic inflammation, opens the way to treat neurodegenerative diseases by targeting systemic disease or interrupting the signalling pathways that mediate the CNS response to systemic inflammation. Both lifestyle changes and pharmacological therapies could, therefore, provide efficient means to slow down or halt neurodegeneration.
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The authors' research work is supported by grants from Alzheimer's Society and Alzheimer's Research Trust UK (V.H.P. and C.H.), and by funding from the Medical Research Council and Wellcome Trust (V.H.P.).
V.H.P. and C.H. have received an independent investigator grant from Pfizer to determine the safety and tolerability of etanercept in patients with Alzheimer disease.
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Perry, V., Holmes, C. Microglial priming in neurodegenerative disease. Nat Rev Neurol 10, 217–224 (2014). https://doi.org/10.1038/nrneurol.2014.38
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