U1-70K and U1A and tau pathogenesis in demented and non-demented individuals with Down syndrome.

Splicing protein mislocalization is associated with tau pathogenesis, but its role in Down syndrome (DS) is under-investigated. Spliceosome associations with tau and plaque pathology were examined in frontal cortex from DS with dementia (DSD+) and without dementia (DSD-) using quantitative immunoblotting and immunohistochemistry. U1-70K and U1A levels were downregulated, and hnRNPA2B1, 3Rtau, and 4Rtau were upregulated, whereas SRSF2 and CLK1 were unchanged in DSD+. The number of U1-70K lightly labeled cells was only greater in layer III in DSD+. U1A intensely stained nuclei decreased significantly in layer III in DSD+, whereas those lightly labeled significantly increased in layers III and V-VI in DSD+. U1 mislocalization and tangles appeared in each laminae examined in both DS groups but were significantly greater in DSD+. Mislocalized U1s that co-localized with AT8, and not TauC3, were significantly increased in DSD+. U1 splicing proteins play a key role in tau pathogenesis in individuals with DS. U1 mislocalization and tangle-like profiles appeared in frontal cortex layer III and V-VI neurons in Down syndrome (DS). Frontal cortex hnRNPA2B1 nuclear morphometric values decreased in layer III in DS with dementia. Frontal cortex SRSF2 and CLK1 nuclear proteins were unchanged in DSD+ and without dementia (DSD-).