Pin 1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in A lzheimer's disease

Aims Neurodegeneration in A lzheimer's disease ( AD ) is characterized by pathological protein aggregates and inadequate activation of cell cycle regulating proteins. Recently, Smad proteins were identified to control the expression of AD relevant proteins such as APP , CDK 4 and CDK inhibitors, both critical regulators of cell cycle activation. This might indicate a central role for Smads in AD pathology where they show a substantial deficiency and disturbed subcellular distribution in neurones. Still, the mechanisms driving relocation and decrease of neuronal Smad in AD are not well understood. However, Pin 1, a peptidyl‐prolyl‐cis/trans‐isomerase, which allows isomerization of tau protein, was recently identified also controlling the fate of Smads . Here we analyse a possible role of Pin 1 for Smad disturbances in AD . Methods Multiple immunofluorescence labelling and confocal laser‐scanning microscopy were performed to examine the localization of Smad and Pin 1 in human control and AD hippocampi. Ectopic Pin 1 expression in neuronal cell cultures combined with W estern blot analysis and immunoprecipitation allowed studying Smad level and subcellular distribution. Luciferase reporter assays, electromobility shift, RNAi ‐technique and qRT ‐ PCR revealed a potential transcriptional impact of Smad on Pin 1 promoter. Results We report on a colocalization of phosphorylated Smad in AD with Pin 1. Pin 1 does not only affect Smad phosphorylation and stability but also regulates subcellular localization of Smad2 and supports its binding to phosphorylated tau protein. Smads , in turn, exert a negative feed‐back regulation on Pin 1. Conclusion Our data suggest both Smad proteins and Pin 1 to be elements of a vicious circle with potential pathogenetic significance in AD .