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Old-Age Interfer(on)ing

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Science Translational Medicine  03 Sep 2014:
Vol. 6, Issue 252, pp. 252ec151
DOI: 10.1126/scitranslmed.3010263

Proper immunity against pathogens, although essential for human life, can exhibit a dark side when the powers of immune cells become detrimental to the host. The tight control of these destructive immune powers is particularly important in the brain, in which neuronal function depends on the careful regulation of potentially harmful microglia (brain macrophages) and durability of the blood-brain barrier, which shields neurons from immediate exposure to chemicals and pathogens in the blood. Recent findings from Baruch et al. show that cells in the choroid plexus (CP)—which separates the human brain from the circulation, and thus the rest of our body—could damage neurons during aging.

Among various mediators of immune responses, polypeptides of the interferon family play a chief role in balancing the precarious act of destroying pathogens while leaving the inner sanctum of the body largely intact. Baruch et al. found an age-related perversion in the CP barrier function that shifts from an interferon type II (IFN-II) protective response to an IFN-I response. The latter is injurious to neurons. Cognitive-function analysis in mice that are deficient for IFN-II signaling revealed that IFN-II–dependent processes are crucial for maintaining normal brain function during aging. Activation of IFN-I, on the other hand, leads to a decrease in CP production of neurotrophic factor, which is essential for neuronal proliferation and survival during aging. Moreover, the authors were able to reverse age-associated cognitive impairments in mice by specifically blocking IFN-I signaling within the brain. Restored cognitive function in the new object recognition task in these mice was associated with increased anti-inflammatory gene expression, enhanced neurogenesis, and a reduction in glial activation (a sign of neuroinflammation frequently associated with neurodegeneration) in the hippocampus.

These data suggest that the ability to neutralize IFN-I responses in the aging brain might provide a powerful tool to curb age-associated cognitive decline in humans. Last, because the mechanisms that govern type II versus type I IFN regulation are well known and numerous genetic variants in the human population have been associated with abnormal IFN responses, these regulatory variants could be used to determine the underlying mechanisms of age-associated cognitive changes in humans.

K. Baruch et al., Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science, published online 21 August 2014 (10.1126/science.1252945). [Abstract]

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