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Survival and plasticity in the aging brain

Research summary:

The general aim of the laboratory is to understand the mechanisms behind the decline in cognitive capacity that occurs during aging. Cognitive decline is not identical in all individuals and clear associations exist between the rate and severity of cognitive decline and the individual’s heritable traits and lifestyle. At the molecular level, the aging phenotype is the consequence of a combination of deficits at multiple levels: mitochondria, protein synthesis and protein quality control machineries, degradation of cellular waste, carbohydrate and triglyceride metabolic pathways for ATP production, hormone synthesis, stem cell renewal, cell membrane organization. In most individuals brain cells cope relatively well with these deficits, only resulting in the mild and common symptoms of aging, such as forgetfulness, decreased ability to maintain focus and decreased problem solving capability. In many others however, these changes accumulate and progress resulting in more serious symptoms and conditions, such as dementia and depression or even Alzheimer’s disease. It then appears that the fine dissection of the causes and mechanisms behind cognitive decay in the aged that we pursue, may facilitate the understanding of the causes and mechanisms involved in pathological cognitive decay. We approach this question by investigating, through biochemical, molecular, electrophysiological and behavioral approaches, the effect of aging on neuronal plasma membrane-mediated survival and function signaling. Some of our contributions to the field in the recent years are: Trovò. Et al. (2013). Low hippocampal PI(4,5)P2 contributes to reduced cognition in old mice due to loss of MARCKs. Nature Neurosci. 16(4).449 – 455; Martin et al. (2014). Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents.EMBO Mol Med.6. 902-917; Palomer et al. (2016) Neuronal activity controls Bdnf expression via Plycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons. Nature Communications. 7: 11081, 2016; Carlos G. Dotti, Mauricio Martín, César Venero Nuñez. “Uso de derivados azólicos para la reducción de pérdidas cognitivas asociadas al envejecimiento”. Solicitud de Patente. Numero de prioridad: P201431798. País de prioridad: ES. Fecha de prioridad: -Diciembre 2014.


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Last nameNameLaboratoryExt.*e-mailProfessional category
Cabrera MartorellInés1224543Estudiante TFM
Carús CadaviecoMarta1224520marta.carus(at)cbm.csic.esTit.Sup.Activ.Técn.y Profes. GP1
Dotti Carlos1224519cdotti(at)cbm.csic.esE. Profesores de Investigación de Organismos Públicos de Investigación
García RodríguezRaquel1224520rgarcia(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Mendaza RuizSusana 1224519Estudiante TFM
Palomer VilaErnest1224543epalomer(at)cbm.csic.esInvestigador
Rosado FloridoLaura1224520Estudiante TFG

Relevant publications:

  • Pollarolo, G., Schulz, J., Munck, S. and Dotti C.G. (2011). Cytokinesis remnants determine neuronal polarity in vivo. NATURE NEUROSCIENCE, 14, 1525-1533. doi: 10.1038/nn.2976.
  • Sodero, A.,  Sassoe-Pognetto, M., Stegner, D., Nieswandt, R. and Dotti, C.G. (2012). Cholesterol loss during glutamate-mediated excitotoxicity. EMBO JOURNAL, 31(7), 1764-1773. doi: 10.1038/emboj.2012.31
  • Gaertner, A., Fornasiero, E.F., Munck, S., Vennekens, K., Seuntjens, E., Huttner, W.B., Valtorta, F. and Dotti, C.G. (2012). N-cadherin specifies first asymmetry in developing neurons. EMBO JOURNAL. 31, 1893-2003. doi: 10.1038/emboj.2012.41.
  • Trovò. L., Ahmed, T., Buzzi, A., Callaerts-Vegh, Z., Bagni, C., Chua, M. VandenDriessche, T., D'Hooge, R., Balschum, D. and Dotti, C.G. (2013). Low hippocampal PI(4,5)P2 contributes to reduced cognition in old mice due to loss of MARCKs. NATURE NEUROSCIENCE, 16(4):449-55. doi: 10.1038/nn.3342
  • Martin MG, Ahmed T, Korovaichuk A, Venero C, Menchón SA, Salas I, Munck S, Herreras O, Balschun D, Dotti CG. (2014). Constitutive hippocampal cholesterol loss underlies poor cognition in old rodents. EMBO MOLECULAR MEDICINE, 6, 902-917. doi: 10.15252/emmm.201303711.
  • Brachet A, Norwoords S, Brouwers JF, Palomer E, Helms JB, Dotti C.G*, Esteban JA. (2015) LTP-triggered cholesterol redistribution activates Cdc42 and drives AMPA receptor synaptic delivery. JOURNAL OF CELL BIOLOGY, 16;208(6):791-806 doi: 10.1083/jcb.201407122. (*co-corresponding, with JA Esteban) 
  • Palomer E, Carretero J, Benvegnu S, Dotti C.G.* & Martin MG. (2016) Neuronal activity controls Bdnf expression via Plycomb de-repression and CREB/CBP/JMJD3 activation in mature neurons. NATURE COMMUNICATIONS 7, 11081-1186. doi: 10.1038/ncomms11081. (*co-corresponding)
  • Palomer, E, Martín-Segura, A, Baliyan, S, Ahmed, T, Balschun, D, Venero, C,  Martin, MG and Dotti, CG. (2016). Aging triggers a repressive chromatin state at BDNF promoters in hippocampal neurons. CELL REPORTS, 16(11):2889-2900. doi: 10.1016/j.celrep.2016.08.028.
  • Benvegnù, S., Mateo, M. I., Palomer, E., Jurado-Arjona, J., and Dotti, C. G. (2017). Aging Triggers Cytoplasmic Depletion and Nuclear Translocation of the E3 Ligase Mahogunin: A Function for Ubiquitin in Neuronal Survival. MOLECULAR CELL, 66(3), 358-372. doi: 10.1016/j.molcel.2017.04.005.
  • Martín-Segura, A., Ahmed, T., Casadomé-Perales, A., Palomares-perez, I., Palomer, E., Kerstens, A., Munck, S., Balschun, D., and Dotti, C.G.(2019). Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization. AGING CELL, 18(3)12932. doi: 10.1111/acel.12932

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