Physiopathology of Alzheimer disease
Javier Vitorica
PhD, Full Professor
Lab members
Marisa Vizuete, PhD Full Professor
Sebastian Jimenez, PhD
Victoria Navarro, PhD
Clara Muñoz-Castro, PhD student
Carmen Romero-Molina, PhD student
Lab contact
Institution
Our projects
The focus of the group is the characterization of microglial and astroglial responses in both murine models of the amyloid beta and Tau pathology of Alzheimer’s disease (AD) and AD patient samples. Based on our recently published data (Navarro et al., 2018; Gutierrez and Vitorica, 2018, Sanchez-Mejias et al., 2016), the microglial response in AD patients seems to be compromised, the causes being diverse, and including the accumulation of soluble forms of phosphorylated Tau (Sanchez-Mejias et al., 2016; Romero-Molina cy col., 2018) or, based on our results this year, the hypoxia associated with vascular pathologies (in collaboration with Dr. A Pascual’s group, IBIS, in preparation). Regardless, AD patients have a clear microglial dysfunction, associated with infiltration of monocyte-derived cells (in preparation), totally absent in the mouse models. We are developing new models that better mimic the microglial dysfunction observed in AD patients. Specifically, we are developing Abeta and Tau models, conditional knockouts of the Csf1R gene specifically in microglial cells with the idea of testing the effect of reducing their survival and function. These models will allow us to establish the role of microglial cells in the development of Abeta and / or Tau pathologies.
On the other hand, we are also characterizing the role of astrocyte activation in pathology. In this sense, and contrary to what might be expected based on their morphology, the astrocytes of both models present a clear pattern of metabolic deficiencies. These deficiencies have been verified by SeaHorse in vitro and, in collaboration with Dr. Barbas Arriba (Analytical Chemistry Area at Universidad San Pablo CEU), the metabolomic analysis of said samples will be carried out.
These objectives are included within a CIBERNED intramural project (IP Javier Vitorica) and have been carried out in collaboration with Dra E. Galea (Marató de TV3). Finally, we have established collaborations to determine, on the one hand, the role of hypoxia in the microglial response in AD pathology and, on the other hand, we are studying the role of possible Trem2 ligands in microglial activation in this pathology
Last publications
Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model. Fernandez-Valenzuela JJ, Sanchez-Varo R, Muñoz-Castro C, De Castro V, Sanchez-Mejias E, Navarro V, Jimenez S, Nuñez-Diaz C, Gomez-Arboledas A, Moreno-Gonzalez I, Vizuete M, Davila JC, Vitorica J, Gutierrez A. Sci Rep 10:14776, 2020. doi: 10.1038/s41598-020-71767-4
Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice. Larramona-Arcas R, González-Arias C, Perea G, Gutiérrez A, Vitorica J, García-Barrera T, Gómez-Ariza JL, Pascua-Maestro R, Ganfornina MD, Kara E, Hudry E, Martinez-Vicente M, Vila M, Galea E, Masgrau R. Mol Neurodegener 15:35, 2020. doi: 10.1186/s13024-020-00382-8.
Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells. García-Bonilla M, Ojeda-Pérez B, García-Martín ML, Muñoz-Hernández MC, Vitorica J, Jiménez S, Cifuentes M, Santos-Ruíz L, Shumilov K, Claros S, Gutiérrez A, Páez-González P, Jiménez AJ. Stem Cell Res Ther 11:121, 2020 doi: 10.1186/s13287-020-01626-6.
Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer’s mice and patients. Sanchez-Mejias E, Nuñez-Diaz C, Sanchez-Varo R, Gomez-Arboledas A, Garcia-Leon JA, Fernandez-Valenzuela JJ, Mejias-Ortega M, Trujillo-Estrada L, Baglietto-Vargas D, Moreno-Gonzalez I, Davila JC, Vitorica J, Gutierrez A. Brain Pathol. 2020 Mar;30(2):345-363. doi: 10.1111/bpa.12785.
Use of human pluripotent stem cell-derived cells for neurodegenerative disease modeling and drug screening platform. Garcia-Leon JA, Vitorica J, Gutierrez A. Future Med Chem. 2019 Jun;11(11):1305-1322. doi: 10.4155/fmc-2018-0520.
Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Boza-Serrano A, Ruiz R, Sanchez-Varo R, García-Revilla J, Yang Y, Jimenez-Ferrer I, Paulus A, Wennström M, Vilalta A, Allendorf D, Davila JC, Stegmayr J, Jiménez S, Roca-Ceballos MA, Navarro-Garrido V, Swanberg M, Hsieh CL, Real LM, Englund E, Linse S, Leffler H, Nilsson UJ, Brown GC, Gutierrez A, Vitorica J, Venero JL, Deierborg T. Acta Neuropathol. 2019 Aug;138(2):251-273. doi: 10.1007/s00401-019-02013-z.
Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology. Romero-Molina C, Navarro V, Sanchez-Varo R, Jimenez S, Fernandez-Valenzuela JJ, Sanchez-Mico MV, Muñoz-Castro C, Gutierrez A, Vitorica J, Vizuete M. Front Cell Neurosci. 2018 Nov 14;12:421. doi: 10.3389/fncel.2018.00421.
Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative. Navarro V, Sanchez-Mejias E, Jimenez S, Muñoz-Castro C, Sanchez-Varo R, Davila JC, Vizuete M, Gutierrez A, Vitorica J. Front Aging Neurosci. 2018 May 11;10:140. doi: 10.3389/fnagi.2018.00140.
Toward a New Concept of Alzheimer’s Disease Models: A Perspective from Neuroinflammation. Gutierrez A, Vitorica J. J Alzheimers Dis. 2018;64(s1):S329-S338. doi: 10.3233/JAD-179914.
Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Gomez-Arboledas A, Davila JC, Sanchez-Mejias E, Navarro V, Nuñez-Diaz C, Sanchez-Varo R, Sanchez-Mico MV, Trujillo-Estrada L, Fernandez-Valenzuela JJ, Vizuete M, Comella JX, Galea E, Vitorica J, Gutierrez A. Glia. 2018 Mar;66(3):637-653. doi: 10.1002/glia.23270.
Javier Vitorica
PhD, Full Professor
Lab members
Marisa Vizuete, PhD, Full Professor
Sebastian Jimenez, PhD
Victoria Navarro, PhD
Clara Muñoz-Castro, PhD student
Carmen Romero-Molina, PhD student
Lab contact
Institution
Our projects
The focus of the group is the characterization of microglial and astroglial responses in both murine models of the amyloid beta and Tau pathology of Alzheimer’s disease (AD) and AD patient samples. Based on our recently published data (Navarro et al., 2018; Gutierrez and Vitorica, 2018, Sanchez-Mejias et al., 2016), the microglial response in AD patients seems to be compromised, the causes being diverse, and including the accumulation of soluble forms of phosphorylated Tau (Sanchez-Mejias et al., 2016; Romero-Molina cy col., 2018) or, based on our results this year, the hypoxia associated with vascular pathologies (in collaboration with Dr. A Pascual’s group, IBIS, in preparation). Regardless, AD patients have a clear microglial dysfunction, associated with infiltration of monocyte-derived cells (in preparation), totally absent in the mouse models. We are developing new models that better mimic the microglial dysfunction observed in AD patients. Specifically, we are developing Abeta and Tau models, conditional knockouts of the Csf1R gene specifically in microglial cells with the idea of testing the effect of reducing their survival and function. These models will allow us to establish the role of microglial cells in the development of Abeta and / or Tau pathologies.
On the other hand, we are also characterizing the role of astrocyte activation in pathology. In this sense, and contrary to what might be expected based on their morphology, the astrocytes of both models present a clear pattern of metabolic deficiencies. These deficiencies have been verified by SeaHorse in vitro and, in collaboration with Dr. Barbas Arriba (Analytical Chemistry Area at Universidad San Pablo CEU), the metabolomic analysis of said samples will be carried out.
These objectives are included within a CIBERNED intramural project (IP Javier Vitorica) and have been carried out in collaboration with Dra E. Galea (Marató de TV3). Finally, we have established collaborations to determine, on the one hand, the role of hypoxia in the microglial response in AD pathology and, on the other hand, we are studying the role of possible Trem2 ligands in microglial activation in this pathology
Last Publications
Enhancing microtubule stabilization rescues cognitive deficits and ameliorates pathological phenotype in an amyloidogenic Alzheimer’s disease model. Fernandez-Valenzuela JJ, Sanchez-Varo R, Muñoz-Castro C, De Castro V, Sanchez-Mejias E, Navarro V, Jimenez S, Nuñez-Diaz C, Gomez-Arboledas A, Moreno-Gonzalez I, Vizuete M, Davila JC, Vitorica J, Gutierrez A. Sci Rep 10:14776, 2020. doi: 10.1038/s41598-020-71767-4
Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice. Larramona-Arcas R, González-Arias C, Perea G, Gutiérrez A, Vitorica J, García-Barrera T, Gómez-Ariza JL, Pascua-Maestro R, Ganfornina MD, Kara E, Hudry E, Martinez-Vicente M, Vila M, Galea E, Masgrau R. Mol Neurodegener 15:35, 2020. doi: 10.1186/s13024-020-00382-8.
Neocortical tissue recovery in severe congenital obstructive hydrocephalus after intraventricular administration of bone marrow-derived mesenchymal stem cells. García-Bonilla M, Ojeda-Pérez B, García-Martín ML, Muñoz-Hernández MC, Vitorica J, Jiménez S, Cifuentes M, Santos-Ruíz L, Shumilov K, Claros S, Gutiérrez A, Páez-González P, Jiménez AJ. Stem Cell Res Ther 11:121, 2020 doi: 10.1186/s13287-020-01626-6.
Distinct disease-sensitive GABAergic neurons in the perirhinal cortex of Alzheimer’s mice and patients. Sanchez-Mejias E, Nuñez-Diaz C, Sanchez-Varo R, Gomez-Arboledas A, Garcia-Leon JA, Fernandez-Valenzuela JJ, Mejias-Ortega M, Trujillo-Estrada L, Baglietto-Vargas D, Moreno-Gonzalez I, Davila JC, Vitorica J, Gutierrez A. Brain Pathol. 2020 Mar;30(2):345-363. doi: 10.1111/bpa.12785.
Use of human pluripotent stem cell-derived cells for neurodegenerative disease modeling and drug screening platform. Garcia-Leon JA, Vitorica J, Gutierrez A. Future Med Chem. 2019 Jun;11(11):1305-1322. doi: 10.4155/fmc-2018-0520.
Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease. Boza-Serrano A, Ruiz R, Sanchez-Varo R, García-Revilla J, Yang Y, Jimenez-Ferrer I, Paulus A, Wennström M, Vilalta A, Allendorf D, Davila JC, Stegmayr J, Jiménez S, Roca-Ceballos MA, Navarro-Garrido V, Swanberg M, Hsieh CL, Real LM, Englund E, Linse S, Leffler H, Nilsson UJ, Brown GC, Gutierrez A, Vitorica J, Venero JL, Deierborg T. Acta Neuropathol. 2019 Aug;138(2):251-273. doi: 10.1007/s00401-019-02013-z.
Distinct Microglial Responses in Two Transgenic Murine Models of TAU Pathology. Romero-Molina C, Navarro V, Sanchez-Varo R, Jimenez S, Fernandez-Valenzuela JJ, Sanchez-Mico MV, Muñoz-Castro C, Gutierrez A, Vitorica J, Vizuete M. Front Cell Neurosci. 2018 Nov 14;12:421. doi: 10.3389/fncel.2018.00421.
Microglia in Alzheimer’s Disease: Activated, Dysfunctional or Degenerative. Navarro V, Sanchez-Mejias E, Jimenez S, Muñoz-Castro C, Sanchez-Varo R, Davila JC, Vizuete M, Gutierrez A, Vitorica J. Front Aging Neurosci. 2018 May 11;10:140. doi: 10.3389/fnagi.2018.00140.
Toward a New Concept of Alzheimer’s Disease Models: A Perspective from Neuroinflammation. Gutierrez A, Vitorica J. J Alzheimers Dis. 2018;64(s1):S329-S338. doi: 10.3233/JAD-179914.
Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Gomez-Arboledas A, Davila JC, Sanchez-Mejias E, Navarro V, Nuñez-Diaz C, Sanchez-Varo R, Sanchez-Mico MV, Trujillo-Estrada L, Fernandez-Valenzuela JJ, Vizuete M, Comella JX, Galea E, Vitorica J, Gutierrez A. Glia. 2018 Mar;66(3):637-653. doi: 10.1002/glia.23270.