title: Nitric oxide and sphingolipids control apoptosis and autophagy with a significant impact on Alzheimer's disease.
abstract: Aberrant regulation of signalling pathways promoting and regulating apoptosis and autophagy contributes to the development of most human neurodegenerative diseases characterised by progressive dysfunction and death of neuronal and glial cells. Both in central and peripheral nervous systems cell death is either apoptotic or autophagic, depending on the cellular setting and the initial pathogenic cue. While some mixed phenotypes have been reported, apoptosis and autophagy tend to develop into mutually exclusive ways to such an extent that they inhibit each other. The sphingolipid ceramide is a key intracellular signalling molecule involved in many cellular processes leading to either survival or death; in most of these processes also the short-lived gaseous messenger nitric oxide (NO) plays a crucial role. The crosstalk between these two messengers and their downstream mediators has been thus extensively investigated and we now have a deep understanding of it and of its multiple feedback controls. What we provide here are details on how NO- and sphingolipid-dependent signalling and their crosstalk impact on degenerative brain diseases, in particular Alzheimers disease; we also describe how the ability of these molecules to regulate autophagy and apoptosis plays a significant role in determining the pathogenic evolution of these diseases. The evidence reported in this review suggests that targeting the NO and sphingolipid-dependent signalling pathways is worth exploiting in therapeutic perspective. In order to pursue these strategies, however, we still need to understand conclusively how the crosstalk between the NO and ceramide/sphingolipid pathways balances towards beneficial vs. toxic effects. In view of the nature of the signalling pathways involved and their multiple roles, the type of crosstalk involved is complex and intermingled with other signalling pathways.
authors.affiliation: Department for Innovation in Biological, Agro-food and Forest systems (DIBAF), Universita' della Tuscia, Viterbo, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Cervia
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Universita' di Milano, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Perrotta
authors.affiliation: Morphology Unit, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Universita' di Milano, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Moscheni
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Universita di Milano, Milano, Italy.
authors.forename: C
authors.initials: C
authors.lastname: De Palma
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences, University Hospital L. Sacco, Universita di Milano, Milano, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Clementi