Progranulin (PGRN) is a widely expressed protein with diverse biological functions. We generated a transgenic mouse overexpressing PGRN and found significantly elevated expression in the forebrain. To explore the neuroprotective capacity of PGRN, we measured brain infarct volume and functional recovery in wild type and transgenic mice following middle cerebral artery occlusion (MCAo). Both neurological and motor functions were rescued by PGRN overexpression, as behaviors recovered more rapidly and to a greater extent following ischemia in PGRN transgenic mice and in wild type mice injected with lentivirus-PGRN. Furthermore, infarct volumes were smaller in transgenic mice compared to wild type (WT) mice as revealed by computerized image analysis. Glial cells overexpressing PGRN were protected from LPS-induced cytotoxicity in vitro. Seven days after LPS treatment, the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) was lower in glial cells cultured from PGRN-overexpressing mice compared to glia from WT mice, while expression of the anti-inflammatory cytokine IL-10 was upregulated in glial cells from transgenic mice. Our results demonstrate consistent and significant improvements in postischemic neurological functions in mice overexpressing PGRN, possibly due to reduced pro-inflammatory cytokine release and elevated anti-inflammatory cytokine release. Progranulin is a promising endogenous neuroprotectant with anti-apoptotic and anti-inflammatory properties.
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