Effects of wild-type and mutant TDP-43 on cognitive function and hippocampal neurons in mice

This study investigates the effects of wild-type (wt) TDP-43 and mutant TDP-43^A315T on cognitive function in C57BL/6J mice and hippocampal neurons (HT22 cells), focusing on the roles of progranulin (PGRN) and Caspase-3 in this process. C57BL/6J mice were injected with lentivirus (TDP-43 wt, TDP-43^A315T, or control) into the hippocampus. Cognitive function was evaluated using the novel object recognition and Y-maze tests. TDP-43 expression and neuronal damage were assessed through immunofluorescence and Nissl staining. PGRN and Caspase-3 expression were quantified by Western blot. In vitro, HT22 cells were transfected with TDP-43 wt or TDP-43^A315T plasmids, and cell viability, survival time, mitochondrial morphology, and protein expression were analyzed. In vivo, both TDP-43 wt and TDP-43^A315T groups exhibited impaired cognitive function, although TDP-43^A315T did not significantly affect performance relative to controls. Immunofluorescence demonstrated increased TDP-43 expression in both experimental groups, while Nissl staining revealed substantial neuronal damage in the TDP-43 wt group. Western blotting showed reduced PGRN and Caspase-3 protein expression in both groups. In vitro, both TDP-43 wt and TDP-43^A315T groups exhibited decreased cell viability, along with significant mitochondrial swelling and damage. Both TDP-43 groups also showed lower PGRN and Caspase-3 protein levels and higher TDP-43 mRNA expression. These findings suggest that both TDP-43 wt and TDP-43^A315T contribute to neuronal damage and suppress PGRN and Caspase-3 expression, which may play a role in the pathogenesis of TDP-43-related neurodegenerative diseases. In all, we explored the potential mechanism differences by comparing the cell damage, protein expression and mitochondrial damage in vivo and in vitro. This comparison is helpful to reveal the pathogenic mechanism of TDP-43^A315T and provide new targets for disease diagnosis and treatment.