Pathogenic mechanisms of Alzheimer’s disease
Research summary:
To identify genes and mechanisms involved in the neurodegeneration characteristic of Alzheimer's disease (AD), we developed cell models that reflect different aspects of the pathogenesis of the disease. These models allow us to identify new genes/functions associated with AD, which could be therapeutic targets for the disease. To do this, we analyze differential gene expression in the models and develop genetic association studies and biomarkers in clinical samples. In recent years, we have focused on models of herpes simplex virus 1 (HSV-1) infection that present characteristic markers of AD, including alterations in the trafficking, metabolism and proteolysis of the amyloid precursor protein (APP), as well as in the phosphorylation of the tau protein.
The study of the lysosome autophagy pathway in these models indicates that HSV-1, especially in the presence of oxidative stress, profoundly affects the final stages of the pathway, causing an increase in lysosomal content accompanied by a significant reduction in the activity of different cathepsins and in the degradation of lysosomal substrates. The evidence that another alpha-herpesvirus with neurotropic properties, HSV-2, induces the same neurodegeneration markers as HSV 1, supports the possible involvement of various infectious agents like as herpesviruses in AD-associated neurodegeneration.
The results of the functional and genetic/biomarker association studies developed so far support the hypothesis that lysosomal function failure could constitute a relevant mechanism in HSV-1-induced neurodegeneration and, in general, in AD type neurodegeneration, so our group is focused on the study of this functional pathway. Currently, we are developing more complex cell models, based on human NPCs, to validate our previous findings in a more physiological environment and delve deeper into the mechanisms involved.
In addition, we participate in several collaborative projects. The most numerous are those aimed to study the genetic architecture of AD, within the framework of the Spanish Consortium for Dementia Genetics (DEGESCO) and the international consortia EADB and IGAP, which continue to reveal new factors and relevant functions in the pathogenesis of this disease.
LUHMES neurons on day 7 of differentiation labeled with MAP2 (red) and B-III tubulin (green) specific antibodies. DAPI-stained nuclei are also shown.
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Aldudo Soto | Jesús | 410 | 4674 | jaldudo(at)cbm.csic.es | Contratado Doctor CIBER |
| Bullido Gómez-Heras | Mª Jesús | 410/114.2 | 4567/ 4674 | mjbullido(at)cbm.csic.es | Profesor Titular Universidad, GA |
| Recuero Vicente | María | 410 | 4674 | mrecuero(at)cbm.csic.es | Contratado Doctor CIBER |
| Salgado Fuentes | Blanca | 410 | 4674 | bsalgado(at)cbm.csic.es | Contrato Predoctoral |
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)
