Reactive gliosis and abnormal hippocampal neurogenesis in TDP-43-ΔNLS transgenic mice

PINO DELGADO, N; DOMBROVSKY, N; ALFIERI, J; KAZLAUSKAS, N; DEPINO AM; WEISSTAUB, N; MÜLLER IGAZ, L

Huerta Grande

Congreso; XXVIII Congreso Anual de la Sociedad Argentina de Investigación en Neurociencias; 2013

Sociedad Argentina de Investigación en Neurociencias

Recent studies demonstrated that Tar-DNA Binding Protein 43 (TDP-43) is a major disease protein in a group of neurodegenerative disorders now collectively referred to as TDP-43 proteinopathies. In these conditions, TDP-43 is redistributed from its normal nuclear localization to form cytoplasmic insoluble aggregates. In order to study TDP-43 pathophysiology, we are using novel transgenic mice with cytoplasmic inducible neuronal expression of human TDP-43 (hTDP-43-ΔNLS). We are currently assessing the development of inflammatory processes at different time points after transgene induction (TI) in specific brain areas of these mice. Double immunofluorescence (IF) with CD11b/ human (h) TDP-43 antibodies revealed activated microglia in the dentate gyrus (DG) of the hippocampus as early as 2 weeks after TI. At 4 weeks, there is an increase in microgliosis in DG and cortex, which later decreases throughout the neurodegeneration process. Astrogliosis was measured using double IF for GFAP/hTDP-43. In addition, recent evidence suggests that TDP-43 might transcriptionally regulate cell-cycle genes. We are evaluating adult neurogenesis in transgenic mice 1 month after TI by double IF with BrdU/ hTDP-43 and DCX/hTDP-43 antibodies. We aim to determine the time course of gliosis and reveal how neurodegeneration and neurogenesis are affected by TDP-43 in the context of inflammatory processes, topics that are vital to develop new and more effective therapies for these disorders.