Early degenerative phenotype in iTDP-43^14A mice at P5 in the absence of FTLD-like TDP-43 aggregation.

<p>(A) Monoclonal antibody to human TDP-43 showed expression at P5 remained restricted to previously characterized regions of hippocampus, cortex and striatum. (B) Western blotting of brain lysate of P5 non-transgenic (NT) and iTDP-43^14A demonstrated increased levels of activated caspase 3 in iTDP-43^14A mice. (C) Abundant caspase 3 immunoreactivity in the cortex of iTDP-43^14A mice that was virtually absent in NT mice, suggestive of elevated cell death in iTDP43^14A compared to NT mice. iTDP-43^14A mice were also characterized by increased ubiquitin staining in the upper layers of the cortex compared to NT mice, which upon higher magnification appeared to be completely diffuse and cytoplasmic. (D) Immunohistochemistry for hTDP-43 and p403/404 and immunofluorescence using antibodies to total TDP-43 and p409/410 TDP-43. Significant amounts of cytoplasmic hTDP-43 were observed in iTDP-43 mice (arrowheads). Note that this cytoplasmic staining was also observed in NT mice (arrowheads) with antibodies to total TDP-43 (tTDP-43 Ab1) and TDP-43 phosphorylated at 409/410 (p409/410). Scale bars in D = 50 µm.