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

NIEVA GV; SILVA PR; IGAZ LM

Los Angeles

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

Alzheimer´s Association

Background: Microglia-driven neuroinflammation andastrocytosis can play an important role in the pathophysiology ofneurodegenerative disorders. Frontotemporal dementia (FTD) and amyotrophic lateralsclerosis (ALS) are two neurodegenerative diseases associated tomislocalization and aggregation of the protein TDP-43. However, therelationship between abnormal TDP-43 metabolism and gliosis is still unclear.We generated and characterizedtransgenic (TG) mice conditionally overexpressing eithernuclear (WT) or cytoplasmic (ΔNLS) forms of human TDP-43 inforebrain neurons. Both animal models show behavioral abnormalities after 1month of TG induction.In this study, we analyzed regional gliosis in these animal models of TDP-43proteinopathies.Methods: Our two mouse models (hTDP-43-WTor hTDP-43-ΔNLS)were raised on doxycycline to repress TG expression until weaning at postnatalday 28. Microglial (Iba1) and astrocytic (GFAP) markers were used for analyzingbrains by immunofluorescence after 1 month of TG expression. Images wereacquired by conventional fluorescence or structured illumination microscopy andquantified using Image J software.Results: hTDP-43-WT micedisplayed higher levels of microglial activation in hippocampal CA1region and somatosensory cortex (SSC) respect to controls, with no differences in motor (MC) and prefrontal (PFC)cortices. hTDP-43-ΔNLS mice showed significant increasesin total % Iba1+ area, microglial cell number and Iba+ cells with activatedmorphology (larger somatic area) in SSC and CA1 region compared to controls. Inaddition, there was a significant increase in mean Iba+ soma area in SSC. PFCdisplayed no significant differences in any of the parameters analyzed. GFAPstaining demonstrated a significant increase in GFAP+ area in all cortical regionsof hTDP-43-WT mice, but not in hippocampalCA1 or dentate gyrus. Finally, hTDP-43-ΔNLS mice showed significantly higher GFAP+ area than controls in allcortical and hippocampal areas analyzed.Conclusions: Bothanimal models show a robust early gliosis in areas where the TG is expressed.However, hTDP-43-DNLSseem to have a more widespread regional astrogliosis and microgliosis profile. These results expand our understanding ofthe relationship between early-stage neuroinflammatory processes and behavioraldeficits in TDP-43 animal models of FTD/ALS. This in turn will help elucidatethe underlying mechanisms of these and other TDP-43 proteinopathies.