Regional and temporal assessment of neurodegeneration in inducible TDP-43-WT transgenic mice.

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

Mar del Plata

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

Sociedad Argentina de Investigación en Neurociencias (SAN)

Neurodegenerative diseases such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are characterized by neuronal inclusions mainly composed of insoluble Transactive Response DNA-binding Protein 43 (TDP-43). We developed a transgenic mice model with inducible overexpression of human wild-type TDP 43 protein (hTDP-43-WT) in forebrain neurons, which recapitulate several features of TDP-43 proteinopathies. These animals develop time-dependent brain weight loss and dentate gyrus (DG) neurodegeneration. In the present study we analyzed in detail the region-specific neuronal loss, at early (1 month) and late (6 months) time points of transgene (TG) induction. Using immunofluorescence against NeuN (a marker of mature neurons), we measured the total width and NeuN-positive cell count in three cortical regions (motor, somatosensorial and prefrontal) and in two hippocampal structures (CA1 and DG). The results show mild neurodegeneration on prefontal cortex, CA1 and DG with absence of neuronal loss on both motor and somatosensorial cortices after 1 month of TG induction. These results are consistent with the early behavioral phenotype observed in hTDP-43-WT mice, displaying spatial and work memory deficits but normal motor performance. Preliminary results of the late time point in the same structures indicates more extensive neurodegeneration. Ours findings contribute to our understanding of the pathological mechanisms underlying these TDP-43 proteinopathies.