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 May 01 TA - eneuro PG - ENEURO.0061-14.2015 VI - 2 IP - 3 4099 - http://www.eneuro.org/content/2/3/ENEURO.0061-14.2015.short 4100 - http://www.eneuro.org/content/2/3/ENEURO.0061-14.2015.full SO - eneuro2015 May 01; 2 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, and 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 the hippocampus. Exercise did not increase brain progranulin mRNA or protein in multiple regions, nor did it increase plasma progranulin, in 4- to 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.