Long-term endurance running activity causes pulmonary changes depending on the receptor for advanced glycation end-products.

The receptor for advanced glycation end-products (RAGE) is an immunoglobulin superfamily cell adhesion molecule predominantly expressed in the lung, but its pulmonary importance is incompletely understood. Since RAGE alters the respiratory mechanics, which is also challenged by endurance running activity, we studied the RAGE-dependent effect of higher running activity on selected lung parameters in a long-term animal model using wild-type (WT) and RAGE knockout (RAGE-KO) mice. Higher long-term running activity of mice was ensured by providing a running wheel for 8 months. Recording the running activity revealed that RAGE-KO mice are more active than WT mice. RAGE-KO caused an increased lung compliance which additionally increased after long-term running activity with minor limitation of the expiratory flow, whereas the respiratory mechanics of WT mice remained constant. Although RAGE-KO mice had a less dense alveolar-capillary barrier for immune cells, higher long-term running activity led only in WT mice to more leukocyte infiltrations in the lung tissue and aggregations of lymphoid cells in the airways. In this regard, WT mice of the activity group were also more sensitive to ventilation-mediated airway damages. In contrast to RAGE-KO mice of the activity group, lungs of WT mice did not show an increase in the cAMP response element-binding protein, a transcription factor regulating many pro-survival genes. Our findings suggest an important role of RAGE in the physical capability due to its effect on the lung compliance as well as RAGE as a mediator of airway damages caused by higher long-term running activity.

Pin1 promotes degradation of Smad proteins and their interaction with phosphorylated tau in Alzheimer's disease.

AIMS: Neurodegeneration in Alzheimer'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, CDK4 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, Pin1, 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 Pin1 for Smad disturbances in AD. METHODS: Multiple immunofluorescence labelling and confocal laser-scanning microscopy were performed to examine the localization of Smad and Pin1 in human control and AD hippocampi. Ectopic Pin1 expression in neuronal cell cultures combined with Western 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 Pin1 promoter. RESULTS: We report on a colocalization of phosphorylated Smad in AD with Pin1. Pin1 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 Pin1. CONCLUSION: Our data suggest both Smad proteins and Pin1 to be elements of a vicious circle with potential pathogenetic significance in AD.