Cell cycle and p38 MAPK activation in aging neurons: physiological role and relation to AD.

We are investigating the role of the p38 MAPK signaling pathway in neurodegeneration and age-related pathologies such as Alzheimer disease. We have analyzed the expression and activation of p38 MAPK family members in the hippocampus and cortex of ageing mice, as well as in rat hippocampal slices and in mouse cortical neurons in culture. In all cases, we have observed that aging correlates with increased levels of p38 MAPK activation. Enhanced levels of phosphorylated p38 MAPK and its activator MKK6 have been also observed in brains of Alzheimer disease patients. Moreover, by performing histological analysis of brain samples, we have observed higher numbers of degenerative neurons in p38α-deficient mice compared with wild-type mice. To evaluate the role in p38α in neurodegeneration in vivo, we are using the 5xFAD mouse model. In particular, we are studying how the downregulation of p38a specifically in the brain affects the behavior of 5xFAD-expressing mice. Our preliminary results suggest that p38 MAPK signaling could be involved in normal and pathological neuronal ageing.

Cell cycle re-entry of neurons is a common phenomenon leading to neurodegenerative disorders, which is often accompanied by the unscheduled activation of CDK family kinases. We have analyzed the expression of different RINGO proteins, a family of atypical CDK activators, in mouse and human brain. We found that RingoA is mostly expressed in the cortex, whereas RingoB is detected preferentially in the hippocampus. RingoA expression is also detected in human brains and rat hippocampal slices. We are investigating the potential implication of RINGO proteins in cell cycle regulation in neurons.