Phosphorylated Smad 2/3 co-localizes with phospho-tau inclusions in Pick's disease, progressive supranuclear palsy and corticobasal degeneration but not with alpha-synuclein inclusions in multiple system atrophy or dementia with Lewy bodies

Impaired transduction of transforming growth factor-[beta] signaling has recently been implicated in Alzheimer disease. Transforming growth factor-[beta] signals are transduced by Smads, which are phosphorylated and translocated to the nucleus, where they initiate gene transcription. In Alzheimer disease, neurofibrillary tangles sequester phosphorylated Smad 2/3 (pSmad2/3) and reduce its nuclear translocation. We have now investigated the relationship between pSmad2/3 and phospho-tau in 3 other tauopathies, Pick disease, progressive supranuclear palsy, and corticobasal degeneration, and in 2 [alpha]-synucleinopathies, dementia with Lewy bodies and multiple system atrophy. In Pick disease, progressive supranuclear palsy, and corticobasal degeneration, pSmad2/3 was demonstrated in neuronal and glial nuclei but also colocalized with cytoplasmic tau inclusions. No pSmad2/3 was detected in glial cytoplasmic inclusions in multiple system atrophy or in Lewy bodies in dementia with Lewy bodies. Our data indicate that phospho-tau but not [alpha]-synuclein cytoplasmic inclusions bind pSmad2/3. The preservation of neuronal nuclear pSmad2/3 in Pick disease, progressive supranuclear palsy, and corticobasal degeneration suggests that cytoplasmic sequestration of pSmad2/3 is likely to have less impact on transforming growth factor-[beta] signal transduction in these diseases than in Alzheimer disease.