PT - JOURNAL ARTICLE AU - Andrew E. Arrant AU - Aashka R. Patel AU - Erik D. Roberson TI - Effects of Exercise on Progranulin Levels and Gliosis in Progranulin-insufficient Mice AID - 10.1523/ENEURO.0061-14.2015 DP - 2015 Jun 22 TA - eneuro PG - ENEURO.0061-14.2015 4099 - http://www.eneuro.org/content/early/2015/06/22/ENEURO.0061-14.2015.short 4100 - http://www.eneuro.org/content/early/2015/06/22/ENEURO.0061-14.2015.full AB - Loss-of-function mutations in progranulin (GRN) are one of the most common genetic causes of frontotemporal dementia (FTD), a progressive, fatal neurodegenerative disorder with no available disease-modifying treatments. Through haploinsufficiency, these mutations reduce levels of progranulin, a protein that has neurotrophic and anti-inflammatory effects. Increasing progranulin expression from the intact allele is therefore a potential approach for treating individuals with GRN mutations. Based on the well-known effects of physical exercise on other neurotrophic factors, we hypothesized that exercise might increase brain progranulin levels. We tested this hypothesis in progranulin heterozygous (Grn+/–) mice, which model progranulin haploinsufficiency. We housed wild-type and progranulin-insufficient mice in standard cages or cages with exercise wheels for 4 or 7.5 weeks, then measured brain and plasma progranulin levels. Although exercise modestly increased progranulin in very young (2-month-old) wild-type mice, this effect was limited to hippocampus. Exercise did not increase brain progranulin mRNA or protein in multiple regions, nor did it increase plasma progranulin, in 4–8-month-old wild-type or Grn+/– mice, across multiple experiments and under conditions that increased hippocampal BDNF and neurogenesis. Grn–/– mice were included in the study to test for progranulin-independent benefits of exercise on gliosis. Exercise attenuated cortical microgliosis in 8-month-old Grn–/– mice, consistent with a progranulin-independent, anti-inflammatory effect of exercise. These results suggest that exercise may have some modest, nonspecific benefits for FTD patients with progranulin mutations, but do not support exercise as a strategy to raise progranulin levels.Significance Statement: Haploinsufficiency of progranulin causes frontotemporal dementia, and strategies to increase progranulin expression from the intact allele could have therapeutic benefit. Here we show that voluntary wheel running under conditions that are sufficient to increase hippocampal BDNF and neurogenesis does not normalize brain or plasma progranulin levels in 4–8 month-old wild-type or Grn+/– mice. However, exercise reduced cortical microgliosis in Grn–/– mice, indicating an anti-inflammatory effect independent of progranulin. These data indicate limited benefits of exercise in the progranulin-insufficient mouse model of frontotemporal dementia without normalization of progranulin levels.