TDP-43-MEDIATED NEURODEGENERATION: ROLE OF INFLAMMATION IN NOVEL TRANSGENIC MODELS OF FTD/ALS.

LIONEL MÜLLER IGAZ

Workshop; First International Workshop of Cuban Network of Neuroimmunology (CUBANNI) and 2nd LatinAmerican Course of Neuroimmunology; 2017

Cuban Network of Neuroimmunology (CUBANNI)

Frontotemporal Dementia (FTD) andamyotrophic lateral sclerosis (ALS) are two human neurodegenerative diseasesassociated to mislocalization and aggregation of the nuclear protein TDP-43. Wehave previously shown in mice that inducible overexpression of human nuclearwild-type TDP-43 protein (hTDP-43-WT) or a cytoplasmically localized form(hTDP-43-NLS) in forebrain neurons evokes neuropathological changes thatrecapitulate several features of TDP-43 proteinopathies. Our results indicate that hTDP-43-NLSmice develop motor abnormalities, including a dramatically altered rotarodperformance, a spontaneous hyperlocomotor phenotype and pathological abnormallimb clasping as early as 2-4 weeks post transgene induction. hTDP-43-NLS micealso showed altered social investigation behavior, a hallmark feature of FTDpatients. Furthermore we found significant deficits in cognitive function innovel object recognition, inhibitory avoidance and Y-maze tests at 1 monthpost-induction. Here, weaimed to study TDP-43 pathophysiology using these novel transgenic mice as amodel for these diseases. Specifically, we are assessing the development ofinflammatory processes in the hippocampus and cortex of these mice, before and throughoutthe neurodegeneration observed at different time points after transgeneinduction (TI). Double immunofluorescence (IF) with CD11b/ human (h)TDP-43 antibodies revealed activated microglia in the dentate gyrus (DG) of thehippocampus as early as 2 weeks after TI. At 4 weeks post TI, there is anincrease in microgliosis in DG and cortex, which later decreases throughoutneurodegeneration progression. Astrogliosis was measured using double IF forGFAP/hTDP-43, with comparable dynamics. We aim to determine the time course ofgliosis and reveal how neurodegeneration is affected by TDP-43 in the context ofinflammatory processes. Theseresults will contribute to address in vivo the pathogenic mechanisms underlyingTDP-43 proteinopathies, which in turn will be vital to develop new and moreeffective therapies for these disorders.