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J Exp Med. 2010 January 18; 207(1): 2–3.
PMCID: PMC2812537

Dementia's inflammatory link

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Brains from progranulin-deficient mice become abnormally inflamed in response to infection.

Inflamed brains pose a danger to themselves, according to a report by Yin and colleagues that identifies a potential link between the immune system and neurodegenerative disease.

Mutations that diminish expression of the protein progranulin cause frontotemporal dementia in humans. Progranulin is involved in various processes, including inflammation suppression, wound healing, embryonic development, and tumorigenesis. But its role in dementia has remained mysterious. Here, Yin et al. show that progranulin may prevent brain cell damage in part by promoting the expression of the anti-inflammatory cytokine IL-10.

In response to Listeria infection, mice that lacked progranulin produced little IL-10 and lots of inflammatory cytokines, including the monocyte chemoattractant MCP-1. Yet despite the elevated response, fewer monocytes were deployed to infected sites, and the mice eventually succumbed to infection. Senior author Aihao Ding explains these counterintuitive results by saying that if alarms were blaring everywhere, police (i.e., monocytes and other leukocytes) wouldn't know where to head.

Microglia, the macrophages of the brain, echoed the body's inflammation in the absence of progranulin. The exaggerated inflammatory response of activated, progranulin-deficient microglia helped trigger neuronal death. Without progranulin, neurons were vulnerable to stresses like oxygen and glucose deprivation—conditions that might occur during a concussion or stroke.

The team's mice never developed the brain atrophy characteristic of patients with frontotemporal dementia. But they did share some features. Levels of ubiquitin and the phosphorylated version of the protein TDP-43 were abnormally high in certain brain regions in the progranulin-deficient mice, indicating some similarity to the ubiquitin- and TDP-43–rich scars that dementia patients acquire. The authors are now investigating whether their mice develop dementia-like behavioral changes.


Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press