title: Effects of Exercise on Progranulin Levels and Gliosis in Progranulin-Insufficient Mice.
abstract: 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 withGRNmutations. 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 orGrn+/-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-oldGrn-/-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.
authors.affiliation: Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Arrant
authors.affiliation: Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Aashka R
authors.initials: AR
authors.lastname: Patel
authors.affiliation: Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama.
authors.forename: Erik D
authors.initials: ED
authors.lastname: Roberson
keywords: BDNF; exercise; frontotemporal dementia; progranulin