Work

Progranulin deficiency exacerbates postoperative cognitive dysfunction via RhoA-mediated axodendritic impairment in aged mice

Year: 2025

Type: article

Abstract: Postoperative cognitive dysfunction (POCD) is a debilitating complication in surgical patients, especially the elderly. yet its molecular mechanisms remain inadequately understood. This study investigates the effects of progranulin (PGRN) on hippocampal neuronal damage and cognitive impairment induced by surgical trauma. Aged mice underwent laparotomy to model POCD, and cognitive function was assessed using the Morris Water Maze and Novel Object Recognition tests. Molecular changes were identified through RNA sequencing. Hippocampal neuronal integrity was evaluated with immunofluorescence, Golgi staining, and transmission electron microscopy. In vitro, HT22 neurons exposed to lipopolysaccharide (LPS) were treated with recombinant PGRN or RhoA-overexpressing lentivirus to investigate mechanistic pathways. Surgery significantly decreased PGRN expression in hippocampal neurons, which was associated with axonal and dendritic damage, cytoskeletal disorganization, and cognitive decline. In LPS-treated HT22 cells, loss of PGRN impaired neurite outgrowth, while exogenous PGRN restored neurite extension by inhibiting RhoA activation. Overexpression of RhoA reversed PGRN’s neuroprotective effects. In vivo, intrahippocampal PGRN administration reduced neuroinflammation, improved axodendritic function, and enhanced cognitive performance in POCD mice. PGRN deficiency drives POCD pathogenesis via RhoA-mediated cytoskeletal dysfunction. Therapeutic targeting of the PGRN-RhoA axis presents a novel strategy to preserve neuronal connectivity and mitigate postoperative cognitive decline in aging populations. • Surgery specifically depletes progranulin (PGRN) in hippocampal neurons, leading to axodendritic damage and persistent cognitive deficits in aged mice. • PGRN deficiency drives cytoskeletal dysfunction and impaired neurite outgrowth by activating RhoA GTPase, a key regulator of actin dynamics. • Therapeutic PGRN administration rescues RhoA-mediated axodendritic impairment, reduces neuroinflammation, and improves cognitive function in a model of postoperative cognitive dysfunction.

Source: Brain Research Bulletin

DOI: 10.1016/j.brainresbull.2025.111649