Editors' ChoiceAlzheimer’s Disease

Neuroinflammation: Friend or foe?

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Science Translational Medicine  11 Feb 2015:
Vol. 7, Issue 274, pp. 274ec27
DOI: 10.1126/scitranslmed.aaa8314

Inflammation is generally considered a bad actor in many disease states, and Alzheimer’s disease (AD) is no exception. Inflammatory cells in the brain, including microglia and astrocytes, congregate around amyloid plaques in AD, releasing cytokines and reactive oxygen species that are thought to damage nearby neurons. Recent large-scale genetic studies have identified genes involved in microglia function as risk factors for AD, including Trem2 and Cd33, focusing the spotlight of AD research on stopping neuroinflammation. With this in mind, two independent groups set out to examine the effect of increasing interleukin-10 (IL-10), an anti-inflammatory cytokine thought to suppress neuroinflammation, in mouse models of AD. To their surprise, IL-10 made matters worse, illustrating the complex relationship between the immune system, amyloid-beta (Aβ), and neurodegeneration.

In concurrent articles in Neuron, research teams headed by Todd Golde (University of Florida) and Terrence Town (University of Southern California) manipulated the expression of IL-10 in transgenic mouse models of AD, which accumulate Aβ and develop amyloid plaques. The Golde group (Chakrabarty et al.) used an injected virus to overexpress IL-10 in the brains of AD mice and observed a striking increase in Aβ and amyloid plaque burden, which was associated with synaptic damage and impaired learning and memory. The Town group (Guillot-Sestier et al.) observed markedly decreased plaque burden, preserved synapses, and improved performance on behavioral tests in AD mice lacking IL-10. IL-10–deficient mice had a more robust inflammatory response around amyloid plaques, and IL-10–deficient microglia were more adept at devouring Aβ. Conversely, the Golde group found that microglia overexpressing IL-10 were less efficient at scavenging Aβ, perhaps due to increased expression of apolipoprotein E, a protein strongly implicated in Aβ metabolism and AD. Finally, the Town group demonstrated increased IL-10 expression in human postmortem brain samples from AD patients, suggesting a possible role for increased IL-10 in AD pathogenesis.

These results from two independent groups illustrate that the innate immune response of the brain in AD is complex and that interventions that may appear promising, such as reducing inflammation with IL-10, may have deleterious consequences on Aβ metabolism. It has long been appreciated that microglia serve as double agents in the AD brain, producing not only damaging inflammatory mediators but also helping to dispose of toxic Aβ. Clearly, therapeutic interventions for AD that target the immune response will need to carefully consider this balance, with a goal of suppressing injurious aspects of inflammation without impairing the ability of glial cells to dispose of Aβ.

M. -V. Guillot-Sestier et al., Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 10.1016/j.neuron.2014.12.068 (2015).[Abstract]

P. Chakrabarty et al., IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 10.1016/j.neuron.2014.11.020 (2015). [Abstract]

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