Monday, 9th December 2019

Tau function and dysfunction in Alzheimer disease


Foto Grupo 2018

Jesús Avila







Research summary:

......  Fig01-300
  Retrovirus labeled granule neurons in the dentate gyrus of Alzheimer disease mouse model.
  Neuroblastoma cells overexpressing tau-GFP (green), stained with anti-EB1 (red). Although both proteins interact with microtubules, tau is a classical MAP that binds along the microtubule lattice, whereas EB1 is a +TIP that associates with microtubule "+" ends.

During years a main objective in our group has been the characterization of the function of the cytoskeletal proteins known as microtubule associated proteins (MAPs). One of these MAPs, MAP1B, is a protein that is mainly located at the axon, in neurons. Now, we have found that MAP1B plays an important role in the development of dendritic spines. On the other hand, we are mainly focusing our studies on other MAP, tau protein. Tau protein appears to play a role in Alzheimer disease and other dementias (tauopathies). Tau protein is a suitable substract for GSK3, a protein kinase also known as tau kinase 1 and that is also related to some features of Alzheimer disease. We have several works about tau and GSK3 and we have isolated, some years ago, a transgenic mouse that overexpresses GSK3. Now, using this mouse, we have studied the neurogenesis at the dentate gyrus. Our results have indicated a decrease in that neurogenesis, in the transgenic mouse, that results in degeneration of dentate gyrus. This degeneration is due to cell death but also to the indicated impaired neurogenesis. These features may be the cause of the memory deficits found in the transgenic mouse. Our actual studies will analyze if the memory impairment found in Alzheimer disease patients are also based in a deficient neurogenesis taking place at the dentate gyrus of the patients.


Relevant publications:

  1. Avila, J., Pallas, N., Bolos, M., Sayas, C. L. & Hernandez, F. (2016) Intracellular and extracellular microtubule associated protein tau as a therapeutic target in Alzheimer disease and other tauopathies, Expert Opin Ther Targets. 20, 653-61.
  2. Jurado-Arjona, J., Llorens-Martin, M., Avila, J. & Hernandez, F. (2016) GSK3beta Overexpression in Dentate Gyrus Neural Precursor Cells Expands the Progenitor Pool and Enhances Memory Skills, J Biol Chem. 291, 8199-213.
  3. Leon-Espinosa, G., Garcia, E., Gomez-Pinedo, U., Hernandez, F., DeFelipe, J. & Avila, J. (2016) Decreased adult neurogenesis in hibernating Syrian hamster, Neuroscience. 333, 181-192.
  4. Llorens-Martin, M., Jurado-Arjona, J., Bolos, M., Pallas-Bazarra, N. & Avila, J. (2016) Forced swimming sabotages the morphological and synaptic maturation of newborn granule neurons and triggers a unique pro-inflammatory milieu in the hippocampus, Brain Behav Immun. 53, 242-54.
  5. Llorens-Martin, M., Teixeira, C. M., Jurado-Arjona, J., Rakwal, R., Shibato, J., Soya, H. & Avila, J. (2016) Retroviral induction of GSK-3beta expression blocks the stimulatory action of physical exercise on the maturation of newborn neurons, Cell Mol Life Sci. 73, 3569-82.
  6. Martin-Maestro, P., Gargini, R., Perry, G., Avila, J. & Garcia-Escudero, V. (2016) PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer's disease, Hum Mol Genet. 25, 792-806.
  7. Medina, M., Hernandez, F. & Avila, J. (2016) New Features about Tau Function and Dysfunction, Biomolecules. 6, E21.
  8. Bolos, M., Llorens-Martin, M., Perea, J. R., Jurado-Arjona, J., Rabano, A., Hernandez, F. & Avila, J. (2017) Absence of CX3CR1 impairs the internalization of Tau by microglia, Molecular neurodegeneration. 12, 59.
  9. Garcia-Ayllon, M. S., Botella-Lopez, A., Cuchillo-Ibanez, I., Rabano, A., Andreasen, N., Blennow, K., Avila, J. & Saez-Valero, J. (2017) HNK-1 Carrier Glycoproteins Are Decreased in the Alzheimer's Disease Brain, Mol Neurobiol. 54, 188-199.
  10. Moreno, H., Morfini, G., Buitrago, L., Ujlaki, G., Choi, S., Yu, E., Moreira, J. E., Avila, J., Brady, S. T., Pant, H., Sugimori, M. & Llinas, R. R. (2016) Tau pathology-mediated presynaptic dysfunction, Neuroscience. 325, 30-8.
  11. Pallas-Bazarra, N., Jurado-Arjona, J., Navarrete, M., Esteban, J. A., Hernandez, F., Avila, J. & Llorens-Martin, M. (2016) Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis, EMBO J. 35, 1417-36.
  12. Ramirez-Rios, S., Denarier, E., Prezel, E., Vinit, A., Stoppin-Mellet, V., Devred, F., Barbier, P., Peyrot, V., Sayas, C. L., Avila, J., Peris, L., Andrieux, A., Serre, L., Fourest-Lieuvin, A. & Arnal, I. (2016) Tau antagonizes EB tracking at microtubule ends through a phosphorylation-dependent mechanism, Mol Biol Cell.
  13. Sanchez-Mut, J. V., Heyn, H., Vidal, E., Moran, S., Sayols, S., Delgado-Morales, R., Schultz, M. D., Ansoleaga, B., Garcia-Esparcia, P., Pons-Espinal, M., de Lagran, M. M., Dopazo, J., Rabano, A., Avila, J., Dierssen, M., Lott, I., Ferrer, I., Ecker, J. R. & Esteller, M. (2016) Human DNA methylomes of neurodegenerative diseases show common epigenomic patterns, Transl Psychiatry. 6, e718.
  14. Bolos, M., Pallas-Bazarra, N., Terreros-Roncal, J., Perea, J. R., Jurado-Arjona, J., Avila, J. & Llorens-Martin, M. (2017) Soluble Tau has devastating effects on the structural plasticity of hippocampal granule neurons, Transl Psychiatry. 7, 1267.
  15. Bolos, M., Perea, J. R. & Avila, J. (2017) Alzheimer's disease as an inflammatory disease, Biomol Concepts. 8, 37-43.
  16. Fuster-Matanzo, A., Jurado-Arjona, J., Benvegnu, S., Garcia, E., Martin-Maestro, P., Gomez-Sintes, R., Hernandez, F. & Avila, J. (2017) Glycogen synthase kinase-3beta regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease, Cell Mol Life Sci. 74, 1153-1163.
  17. Garcia-Escudero, V., Gargini, R., Martin-Maestro, P., Garcia, E., Garcia-Escudero, R. & Avila, J. (2017) Tau mRNA 3'UTR-to-CDS ratio is increased in Alzheimer disease, Neurosci Lett. 655, 101-108.
  18. Gomez-Ramos, A., Picher, A. J., Garcia, E., Garrido, P., Hernandez, F., Soriano, E. & Avila, J. (2017) Validation of Suspected Somatic Single Nucleotide Variations in the Brain of Alzheimer's Disease Patients, J Alzheimers Dis. 56, 977-990.
  19. Lissek, T.A. et al. Building Bridges through Science, Neuron. 96, 730-735.
  20. Medina, M., Khachaturian, Z. S., Rossor, M., Avila, J. & Cedazo-Minguez, A. (2017) Toward common mechanisms for risk factors in Alzheimer's syndrome, Alzheimers Dement (N Y). 3, 571-578.
  21. Rodriguez-Rodriguez, P., Sandebring-Matton, A., Merino-Serrais, P., Parrado-Fernandez, C., Rabano, A., Winblad, B., Avila, J., Ferrer, I. & Cedazo-Minguez, A. (2017) Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons, Brain. 140, 3269-3285.
  22. Sotiropoulos, I., Galas, M. C., Silva, J. M., Skoulakis, E., Wegmann, S., Maina, M. B., Blum, D., Sayas, C. L., Mandelkow, E. M., Mandelkow, E., Spillantini, M. G., Sousa, N., Avila, J., Medina, M., Mudher, A. & Buee, L. (2017) Atypical, non-standard functions of the microtubule associated Tau protein, Acta Neuropathol Commun. 5, 91.
  23. Teixeira, C. M., Avila, J. & Llorens-Martin, M. (2017) Versatile use of rtTA-expressing retroviruses in the study of neurodegeneration, Oncotarget. 8, 10771-10772.
  24. Avila, J. (2018) Our Working Point of View of Tau Protein, J Alzheimers Dis. 62, 1277-1285.
  25. Bolos, M., Perea, J. R., Terreros-Roncal, J., Pallas-Bazarra, N., Jurado-Arjona, J., Avila, J. & Llorens-Martin, M. (2018) Absence of microglial CX3CR1 impairs the synaptic integration of adult-born hippocampal granule neurons, Brain Behav Immun. 68, 76-89.
  26. Hernandez, F., Llorens-Martin, M., Bolos, M., Perez, M., Cuadros, R., Pallas-Bazarra, N., Zabala, J. C. & Avila, J. (2018) New Beginnings in Alzheimer's Disease: The Most Prevalent Tauopathy, J Alzheimers Dis.
  27. Perea, J. R., Avila, J. & Bolos, M. (2018) Dephosphorylated rather than hyperphosphorylated Tau triggers a pro-inflammatory profile in microglia through the p38 MAPK pathway, Experimental neurology. 310, 14-21.
  28. Perez, M., Medina, M., Hernandez, F. & Avila, J. (2018) Secretion of full-length Tau or Tau fragments in cell culture models. Propagation of Tau in vivo and in vitro, Biomol Concepts. 9, 1-11.
  29. Pose-Utrilla, J., Garcia-Guerra, L., Del Puerto, A., Martin, A., Jurado-Arjona, J., De Leon-Reyes, N. S., Gamir-Morralla, A., Sebastian-Serrano, A., Garcia-Gallo, M., Kremer, L., Fielitz, J., Ireson, C., Perez-Alvarez, M. J., Ferrer, I., Hernandez, F., Avila, J., Lasa, M., Campanero, M. R. & Iglesias, T. (2018) Author Correction: Excitotoxic inactivation of constitutive oxidative stress detoxification pathway in neurons can be rescued by PKD1, Nat Commun. 9, 473.


Doctoral Theses:


Noemí Pallas Bazarra (2015).Estudio del papel de la proteína tau en la modulación de la neurogénesis hipocampal adulta.Universidad Autónoma de Madrid. Directors: María Llorens-Martín & Félix Hernández.


Patricia Martín-Maestro (2016). Mitophagy dysfunction in peripherasl and neural models of Alzheimer disease. Universidad Autónoma de Madrid. Directors: Vega García-Escudero & Jesús Avila.


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