Given the potential involvement of nuclear speckle components in tauopathy and co-deposition of pSRRM2 with tau in pathological lesions in AD, we examined the relationship between mis-localization of pSRRM2 and disease severity. First, we tested for associations between pSRRM2 and clinical AD manifestation by comparing age at onset and the presence of pSRRM2 within the neuronal soma in AD frontal cortex where we noted cytoplasmic pSRRM2 in th 72% of AD cases. AD cases bearing cytoplasmic pSRRM2 exhibited a relatively younger age of AD onset (11 years earlier) as compared to cases lacking pSRRM2 mis-localization (Fig. 4a). Next, we examined the relationship between pSRRM2 mis-localization and frontal cortical pTau burden in AD, where we observed a significant increase in pTau abundance in cases with cytoplasmic mis-localization of pSRRM2 compared to cases with normal nuclear distribution (Fig. 4b). Finally, we assessed neurodegeneration through NeuN immunohistochemistry, where we observed increased neuronal loss in AD cases with aberrant cytoplasmic pSRRM2 (Fig. 4c). Taken together, these results demonstrate that cytoplasmic distribution of pSRRM2 appears to coincide with exacerbated AD clinical onset and neuropathological severity.
