Partner 21: CIBERNED-ISCIII. Madrid, Spain

Scientist responsible: Dr Francsico Wandosell

- Neurodegenerative diseases are characterized by the death of neurons in different regions of the nervous system and the subsequent functional deterioration of the affected areas.  The best known examples of such pathologies are Alzheimer’s disease and Parkinson’s disease, although other conditions such as Huntington’s disease, the ataxias, Amyotrophic lateral sclerosis, etc, also belong to the same clinical group.  Neurodegenerative diseases have an enormous impact on the lives of affected individuals and their families, as well as on society as a whole.
The Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) represents the Spanish initiative to combat neurodegenerative diseases.  CIBERNED is a “networked” institute that brings together the best basic and clinical neuroscience research groups.  Its objective is to foster high-quality, co-operative medical research aimed at the prevention and treatment of neurodegeneration.
CIBERNED’s legal structure is that of a consortium; it is formed by the Instituto de Salud Carlos III(Ministry of Science & Innovation) and other public institutions such as the Spanish Scientific Research Council (CSIC), universities, hospitals, etc in cooperation with the governments of Spain’s autonomous communities.
CIBERNED is organised into 6 thematic areas which together cover the different neurodegenerative pathologies. The distribution of the areas shows CIBERNED’s commitment to stimulating translational investigation and obtaining scientific knowledge to aid in the prevention, diagnosis and treatment of neurodegenerative diseases. Taken together, and without diminishing the possibility for transverse research projects to be implemented across the different areas, the objective of this structure is to provide a coherent conceptual scheme by which a tangible, cooperative scientific activity materializes between the different research groups. Naturally, the proposed structure is susceptible to alteration as dictated by the changing nature of CIBERNED

AREA 4- Molecular pathology of Alzheimer’s disease. Neuroinflammation and neurotrophic  4
Alzheimer’s disease (AD) is characterised by the presence of senile plaques and neurofibrillary tangles in the brains of affected patients, together with synapse loss (considered a synaptopathy), fundamentally between hippocampal and cortical neurons, and for the considerable neurodegeneration in evidence. Some aspects of these pathologies can be reproduced in animal and cell models. AD is the most common neurodegenerative disease and one of the most important causes of patient dependence in the Spanish population. Studies carried out by researchers in this area aim to provide a better understanding of the indicated anomalies by looking for neuroprotective agents which prevent the disease, or possible therapeutic agents that correct it. Various groups in this area possess complementary expertise, experience and technological know-how, and as such have been involved in cooperative research activity for some time.

CIBERNED -  AREA 4- GROUP- “Molecular mechanism of Neurodogeneration and regeneration” - Supervisor – Prof.  Francisco Wandosell

Our group is devoted to the analysis of molecular mechanism triggered by neurodegenerative processes. We try to understand key signals that regulate cellular morphogenesis, and how these putative pathways may be defective in some pathological situations. As a second challenge we would like to propose regeneration alternatives. 
In normal neuronal development, we try to understand key signals that regulate neuronal morphogenesis (acquisition of neuronal polarity). Using a model of cultured hippocampal neurons, we have defined that GSK3 and the NF-B inhibitor (IB are essential to form an axon and later they play an important role to maintain the axonal properties, such as the axon initial segment function. Thus, we are trying to define more deeply the mechanisms involved in axon and axon initial segment formation and maintenance, which are critical for the final function of neurons (Supervisor Dr. J.J. Garrido).  In addition, we whish to understand the molecular mechanism that regulates actin polymerization, which is an essential process underlying numerous neuronal functions. We are interesting in regulatory elements such as Rho family proteins, or more specifically in elements controlling actin polymerization such as  WASP-WIP (Supervisor Drª I. Anton).
Analyzing some cellular models of neurodegeneration, we have defined that the increases the activity of glycogen synthase kinase 3 (GSK-3), correlate with neuronal degeneration, and in some cases with neuronal death.  Second, we have defined that an increase of GSK3 activity does not necessarily correlate with neurodegeneration.  In some neurodegeneration mouse models we have defined that the pathway PI3K-Akt-GSK3 is deregulated being responsible, at least in part, of the final neurodegeneration process. On the other hand, we determined that some hormones, such as estradiol modulated neuroprotection through the inhibition of GSK3. Our work is trying to identify elements implicated in this neuroprotective effect  (Supervisor Dr. F. Wandosell).

http://www.ciberned.es/grupofranciscowandosell.aspx
http://www.cbm.uam.es/mkfactory.esdomain/webs/CBMSO/plt_LineasInvestigacion.aspx?IdObjeto=63

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SOME REFERENCES (2004-2009)

- C. Gonzalez-Billault, , et al. (2004). J. Neurobiol. 58 48-59 
- P. Cardona-Gómez, et al. (2004).  Molecular Cell. Neuroscience 25:363-373 
- Del Río, J. A., et al., (2004).  Current Biology, Vol 14, 840-850, 25
- Echeverria V, et al.  (2004). J Alzheimers Dis 6:209-219. 
- Echeverria, et al. (2004).  Neuroscience 129, 583-592 
- M.P. Fache, et al. (2004). Journal of Cell Biology, 166: 571-578       
- González-Billault, C., et al.  (2005).  Cereb Cortex 8,  1134-45     
- M. T. Moreno-Flores, et al. (2006).  Molecular Therapy 13-3: 598-608      
- Pastrana, E., et al., (2006).  J.  Neuroscience 20-20: 5347-59    
- Mendez P.et al. (2006). Frontiers in Neuroendocrinology 27-4: 391-403                                 
- D Simon, O. et al. (2006). In “Glycogen Synthase Kinase 3(GSK-3) and Its Inhibitors”. John Wiley and Sons, Inc.  Edt. by A Martinez, A Castro and M Medina  
- M. Salcedo, et al. (2007). Apoptosis. – 12-2: 395-409 
- F. Lim, et al. (2007). Molecular Therapy15-6: 1072-8                                
- JJ Garrido et al. (2007).FEBS Lett.– 581-8: 1579-86.     
- Anton, I. M et al.(2007).  Trends in Cell Biol 17-11: 555-562
- Sanchez-Ponce D., et al.,  (2008). Mol. Cell. Neurosci., 37 (4): 832-844
- O Varea et al (2009) PLOS One. Accepted