One of the principal goals of biomedical research is to discover novel molecules participating in ageing, neurogenesis, and neurodegeneration, and the characterization of the molecular mechanisms involved in these processes. These studies would help us to better understand neurodegeneration and will improve the possibilities to develop novel therapeutic strategies for the prevention or treatment of neurodegenerative disorders. Our research group is focussed on the study of PKD (Protein Kinase D) and its substrate Kidins220 (Kinase D interacting substrate of 220 kDa), in order to define their role in neuronal physiopathology. Particularly, we are interested in studying the function of these two molecules in neuronal development and maturation, survival and death. Kidins220 is an evolutionary conserved transmembrane protein with unique features, which presents one single gene from C. elegans to humans. We cloned Kidins220 as the first physiological substrate identified for PKD1. Some of the functions of this protein are now starting to be deciphered, being its role as an efector of neurotrophin signalling the better known. We have discovered that Kidins220 is crucial for neuronal survival. Under excitotoxic conditions, such as the ones produced in brain ischemia, it undergoes a strong downregulation mediated by calpain proteolysis. Excitotoxicity is a type of neuronal death induced by toxic concentrations of glutamate through overactivation of N-methyl-d-aspartate receptors (NMDARs) that takes place in acute or chronic cerebral damage, and participates in neuronal loss associated with Alzheimer´s disease and other neurodegenerative diseases. In addition, we have shown that Kidins220 controls axonal establishment and elongation as well as dendritic development and neuronal maturation by binding and modulating microtubule regulatory proteins such as the microtubule associated proteins MAP1B and MAP2. Microtubule disorganization, axonopathies and the alteration of neuronal cytoarchitecture are early events in Alzheimer´s disease pathogenesis. MAP1B and MAP2 are sequestered by hyperphosphorylated tau in neurofibrillary tangles, one of the major hallmarks of this disease. All together, these data led us to hypothesize that Kidins220 could be altered in Alzheimer´s disease. During the last year we have published that Kidins220 is increased in human brain necropsies from Alzheimer´s disease patients. At present, our major interest is to further investigate the molecular mechanisms by which Kidins220 modulates neuronal differentiation, survival and neurodegeneration using cellular and animal models as well as human samples. We aim to determine whether Kidins220 alterations in Alzheimer´s disease could be at the basis of the ethiopathology of this dementia, and to design novel approaches for neuroprotection.