Pathogenic mechanisms of Alzheimer’s disease

Research summary:

To identify genes and mechanisms involved in Alzheimer's disease (AD) neurodegeneration, we have developed cellular models mimicking different aspects of the disease pathogenesis. To identify new genes/functions associated with AD, which could be therapeutic targets for it, we perform differential gene expression analyses in the models, followed by genetic association studies in case‑control samples. Currently, we have models of oxidative stress (OS) and herpes simplex virus (HSV1) infection 1 that present markers characteristic of AD, like the alterations in the traffic, metabolism and proteolysis of the amyloid precursor protein (APP), as well as in the phosphorylation of the tau protein.

The study of the autophagy lysosome pathway in these models has shown us that HSV1 and EO infection profoundly affect the final stages of the route, provoking an increase in the cellular content of lysosomes accompanied by a significant reduction in the degradation of lysosome substrates. The observation that another alpha-herpesvirus with neurotropic properties, HSV2, induces the same markers of neurodegeneration as HSV1, supports the possible involvement of various infectious agents in the neurodegeneration associated with EA. Overall, the results of the functional, gene expression and genetic association studies we have developed so far support the hypothesis that failure of lysosomal function could constitute a relevant mechanism in neurodegeneration, so our group is currently focused on studying this functional route in the cell models.  We have also recently initiated the study of biomarkers related to HSV1 infection, lysosomal function and cholesterol metabolism as predictors of dementia risk in patients with cognitive impairment.

In addition, we participate in several collaborative projects for the search for genetic factors involved in the EA, mainly within the framework of the Spanish Consortium of Dementia Genetics (DEGESCO), as well as the international consortia EADB and IGAP, which continue to reveal new factors relevant roles in the pathogenesis of this disease.

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Oxidative stress produces the accumulation of APP protein and its carboxi and amino terminal fragments in SK N MC neuronal cells.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Aldudo SotoJesús4104674jaldudo(at)cbm.csic.esTco. de Investigación y Laboratorio
Bullido Gómez-HerasMª Jesús410/114.24567/ 4674mjbullido(at)cbm.csic.esProfesor Titular Universidad, GA
Llorente GinésPatricia Pilar4104674Contratado CIBER
Mejías PérezVictor4104674vmejias(at)cbm.csic.esTco. de Investigación y Laboratorio
Pérez GonzálezPaula4104674paula.perez(at)cbm.csic.esTco. Sup.Investig. y Laboratorio, GP3
Recuero VicenteMaría4104674mrecuero(at)cbm.csic.esContratado CIBER

Relevant publications:

  • Kristen, H., Sastre, I., Munoz-Galdeano, T., Recuero, M., Aldudo, J., and Bullido, M.J. (2018). The lysosome system is severely impaired in a cellular model of neurodegeneration induced by HSV-1 and oxidative stress. Neurobiology of aging 68, 5-17.
  • Llorente, P., Kristen, H., Sastre, I., Toledano-Zaragoza, A., Aldudo, J., Recuero, M., and Bullido, M.J. (2018). A Free Radical-Generating System Regulates Amyloid Oligomers: Involvement of Cathepsin B. J Alzheimers Dis 66, 1397-1408.
  • Kunkle, B.W., Grenier-Boley, B., Sims, R., Bis, J.C., Damotte, V., Naj, A.C., Boland, A., Vronskaya, M., van der Lee, S.J., Amlie-Wolf, A., et al. (2019). Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics 51, 414-430.
  • Moreno-Grau, S., de Rojas, I., Hernandez, I., Quintela, I., Montrreal, L., Alegret, M., Hernandez-Olasagarre, B., Madrid, L., Gonzalez-Perez, A., Maronas, O., et al. (2019). Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks: The GR@ACE project. Alzheimers Dement 15, 1333-1347.
  • Itzhaki, R.F., Lathe, R., Balin, B.J., Ball, M.J., Bearer, E.L., Braak, H., Bullido, M.J., Carter, C., Clerici, M., Cosby, S.L., et al. (2016). Microbes and Alzheimer's Disease. J Alzheimers Dis 51, 979-984.
  • Pastor, P., Moreno, F., Clarimon, J., Ruiz, A., Combarros, O., Calero, M., Lopez de Munain, A., Bullido, M.J., de Pancorbo, M.M., Carro, E., et al. (2016). MAPT H1 Haplotype is Associated with Late-Onset Alzheimer's Disease Risk in APOEvarepsilon4 Noncarriers: Results from the Dementia Genetics Spanish Consortium. J Alzheimers Dis 49, 343-352.
  • Kristen, H., Santana, S., Sastre, I., Recuero, M., Bullido, M.J., and Aldudo, J. (2015). Herpes simplex virus type 2 infection induces AD-like neurodegeneration markers in human neuroblastoma cells. Neurobiology of aging 36, 2737-2747.
  • Recuero, M., Munive, V.A., Sastre, I., Aldudo, J., Valdivieso, F., and Bullido, M.J. (2013). A free radical-generating system regulates AbetaPP metabolism/processing: involvement of the ubiquitin/proteasome and autophagy/lysosome pathways. J Alzheimers Dis 34, 637-647.
  • Santana, S., Sastre, I., Recuero, M., Bullido, M.J., and Aldudo, J. (2013). Oxidative stress enhances neurodegeneration markers induced by herpes simplex virus type 1 infection in human neuroblastoma cells. PloS one 8, e75842.

Awards:

  • Fundación Madrid+D. Premio a las mejores patentes; accésit. (2011)
  • Sociedad Madrileña de Neurología. Premio Ramón y Cajal de Investigación básica (2011)

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