Progranulin deficiency promotes persistent neuroinflammation and causes regional pathology in the hippocampus following traumatic brain injury.

Abstract

Traumatic brain injury (TBI) can be progressive and can lead to the development of a long-term complication termed chronic traumatic encephalopathy. The mechanisms underlying the progressive changes are still unknown; however, studies have suggested that microglia-mediated neuroinflammation in response to TBI may play a fundamental role. This study aimed to determine whether progranulin (PGRN), a major modulator of microglial activity, plays a role in the progressive damage following TBI. PGRN-deficient and wild-type mice were subjected to controlled cortical impact and were observed neuropathologically after 3 days, 7 days, and 5months. Compared to sham and wild-type mice, the PGRN-deficient mice showed overall stronger microgliosis and astrocytosis. The astrocytosis involved broader areas than the microgliosis and was more prominent in the basal ganglia, hippocampus, and internal capsule in PGRN-deficient mice. Ongoing neuronal death was uniquely observed in the hippocampal CA3 region of PGRN-deficient mice at 5months after TBI, accompanying the regional chronic microgliosis and astrocytosis involving the CA3 commissural pathway. In addition, there was M1 microglial polarization in the pericontusional area with activated TLR4/MyD88/NF-κB signaling; however, the hippocampus showed only mild M1 polarization 7 days after TBI. Lastly, Morris water maze tests showed PGRN-deficient mice had poorer spatial learning and memory 5months after TBI than wild-type or sham mice. The data indicated the PGRN deficiency caused TBI progression by promoting persistent microgliosis with microglial polarization and astrocytosis, as well as regional pathology in the hippocampus. The study suggests that PGRN should be evaluated as a potential therapy for TBI.