P1‐177: Progranulin deficiency leads to altered microglial function and neuroinflammation

Abstract

Loss-of-function mutations in the progranulin (GRN) gene are a common cause of autosomal dominant frontotemporal lobar degeneration (FTLD), a fatal and progressive neurodegenerative disorder common in people under 65. Progranulin, a pleiotropic protein with diverse roles in the periphery, is expressed in both neurons and microglia, the resident immune cells of the CNS. Haploinsufficiency of progranulin may alter microglial function leading to chronic neuroinflammation and this microglial dysfunction could play a role in FTLD disease pathogenesis. In support of this hypothesis, progranulin-deficient mice have an exaggerated response to inflammatory stimuli and show increased release of inflammatory cytokines from peripheral macrophages. Symptomatic FTLD patients carrying GRN mutations show elevated serum levels of the pro-inflammatory cytokine IL-6. In addition, in the brains both of FTLD patients and of progranulin-deficient mice, there is increased immunoreactivity for markers of activated microglia and reactive astrocytes. Direct evidence as to whether or not microglia exhibit a pro-inflammatory phenotype similar to peripheral macrophages and/or if increased pro-inflammatory cytokine levels are present in the CNS is currently lacking. Primary microglia were isolated from progranulin-deficient and wild-type mice. The cytokine profile of lipopolysaccharide (LPS) stimulated microglial cultures was evaluated using Mesoscale Discovery and enzyme-linked immunosorbent assays (ELISAs). Quantitative polymerase chain reaction was used to quantify cytokine levels in the brain of progranulin-deficient mice. Plasma levels of circulating cytokines were also evaluated by ELISA in these mice. Progranulin-deficient primary microglia showed an altered cytokine profile in response to LPS stimulation in culture. Progranulin-deficient mice also display abnormal plasma cytokine levels and elevated expression of some cytokines in the aged brain. We conclude that progranulin acts as an anti-inflammatory molecule both in the periphery and importantly also in the CNS, and that altered microglial function and chronic neuroinflammation may be important contributors to FTLD disease pathogenesis. Anti-inflammatory therapies may prove beneficial for FTLD patients carrying GRN mutations.