Astrocytosis and microgliosis are early features of conditional mouse models of TDP-43-related frontotemporal dementia.

IGAZ, LIONEL M.; NIEVA, GABRIELA V.; SILVA, PABLO R.

Los Angeles

Conferencia; AAIC 2019 (Alzheimer´s Association International Conference); 2019

Alzheimer´s Association

Background: Microglia-driven neuroinflammation and astrocytosis 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 the protein TDP-43. However, the relationship between abnormal TDP-43 metabolism and gliosis is still unclear. We generated and characterized transgenic (TG) mice conditionally overexpressing either nuclear (WT) or cytoplasmic (ΔNLS) forms of human TDP-43 in forebrain neurons. Both animal models show behavioral abnormalities after 1 month of TG induction. In this study, we analyzed regional gliosis in these animal models of TDP-43 proteinopathies.Methods: Our two mouse models (hTDP-43-WT or hTDP-43-ΔNLS) were raised on doxycycline to repress TG expression until weaning at postnatal day 28. Microglial (Iba1) and astrocytic (GFAP) markers were used for analyzing brains by immunofluorescence after 1 month of TG expression. Images were acquired by conventional fluorescence or structured illumination microscopy and quantified using Image J software.Results: hTDP-43-WT mice displayed higher levels of microglial activation in hippocampal CA1 region and somatosensory cortex (SSC) respect to controls, with no differences in motor (MC) and prefrontal (PFC) cortices. hTDP-43-ΔNLS mice showed significant increases in total % Iba1+ area, microglial cell number and Iba+ cells with activated morphology (larger somatic area) in SSC and CA1 region compared to controls. In addition, there was a significant increase in mean Iba+ soma area in SSC. PFC displayed no significant differences in any of the parameters analyzed. GFAP staining demonstrated a significant increase in GFAP+ area in all cortical regions of hTDP-43-WT mice, but not in hippocampal CA1 or dentate gyrus. Finally, hTDP-43-ΔNLS mice showed significantly higher GFAP+ area than controls in all cortical and hippocampal areas analyzed.Conclusions: Both animal models show a robust early gliosis in areas where the TG is expressed. However, hTDP-43-ΔNLS seem to have a more widespread regional astrogliosis and microgliosis profile. 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.