Regional neurodegeneration and ultrastructural changes in the brain of a conditional TDP-43 mouse model of frontotemporal dementia/amyotrophic lateral sclerosis

LIONEL MULLER IGAZ; FLORENCIA VASSALLU; LAURA CALTANA

Congreso; SAN2022 Meeting; 2022

Sociedad Argentina de Neurociencias

TDP-43 is the main component of the pathological cytoplasmic inclusions found in both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two neurodegenerative diseases for which there is no known cure. TDP-43 is a protein localized in the nucleus and involved in RNA metabolism, among other functions. Our transgenic mice with inducible cytoplasmic expression of TDP-43 in forebrain neurons recapitulate behavioral phenotypes, neurodegeneration and gene expression changes that occur in both diseases. In order to evaluate the early effects of TDP-43-?NLS overexpression, we analyzed presynaptic markers Syntaxin 1 (Stx1) and Synaptophysin (Syn), and cytoskeleton proteins MAP2 (a protein associated to microtubule whose expression is specific to dendrites and cellular bodies) and NF200 (a neurofilament component and axonal marker). TDP-43-?NLS mice showed evidence of decreased hippocampal Stx1 immunoreactivity (IR) in mossy fiber terminals projecting to CA3 and Syn IR in hippocampal CA1 and auditory cortex, suggesting synaptic loss. Study of IR levels for MAP2 and NF200 will reveal axonal and dendritic structure in different cortical areas and hippocampal subfields. The analysis of these neuronal markers will provide further evidence on the pathological abnormalities displayed by this animal model of TDP- 43 proteinopathies, and help us to delineate the early events triggered by mislocalizedTDP-43 before overt neurodegeneration is observed.