Early microgliosis in a conditional mouse model of TDP-43 proteinopathies

LIONEL MULLER IGAZ; PABLO ROBERTO SILVA; GABRIELA VERÓNICA NIEVA

Mar del Plata

Congreso; XXXII Congreso Sociedad Argentina de Investigación en Neurociencia; 2017

Microglia-driven neuroinflammation can play an important role in the pathophysiology of neurodegenerative disorders. Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two neurodegenerative diseases associated to mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43). We developed transgenic mice conditionally overexpressing human wild-type TDP-43 protein (hTDP-43-WT) in forebrain neurons, a model that recapitulate key features of FTD/ALS. After post-weaning transgene induction during 1 month, these mice display impairment in cognitive and social domains in the absence of motor abnormalities. In order to determine whether there is an inflammatory signature when the early behavioral phenotypes are established, we used immunofluorescence analysis of Iba1 staining to characterize the regional microglial cell activation after short-term (1 month) expression of the transgene. hTDP-43-WT mice showed significantly higher levels of microglial activation in hippocampal CA1 region respect to controls. Somatosensory cortex of hTDP-43-WT mice displayed higher Iba1 staining than controls, while there were no significant differences in motor and prefrontal cortices. In sum, these results expand our understanding of the relationship between early-stage neuroinflammatory processes and behavioral deficits in TDP-43 animal models of FTD/ALS. This in turn will help elucidate the underlying mechanisms of these and other TDP-43 proteinopathies.