Degeneration and regeneration of the central nervous system

Dr. Mar Pérez, Dr. Vega García-Escudero & Dr. Mª Teresa Moreno Flores

Understanding the mechanisms underlying neurodegeneration is essential for the success of regenerative therapies. Our research focuses on investigating fundamental aspects of neurodegeneration. Alzheimer’s disease is a neurodegenerative disorder characterized by the accumulation of Tau protein into intracellular neurofibrillary tangles and amyloid-β peptide forming extracellular amyloid plaques. A significant portion of our work is dedicated to studying Tau pathology and its relevance to Alzheimer’s disease and other neurodegenerative conditions. One of our primary objectives is to unravel the functions of different Tau protein domains, as well as its splicing variants and transcriptional modifications.

Cellular stress is a key factor in all neuropathies, with mitochondria playing a central role in this process as both the primary energy-producing organelle and a major source of oxidative stress. Autophagy, the cellular mechanism responsible for recycling molecules and organelles through lysosomal degradation, is fundamental in many neurodegenerative diseases, where protein aggregation is a common feature. We have demonstrated that mitochondrial recycling through autophagy, known as mitophagy, is disrupted in Alzheimer’s disease, leading to the accumulation of dysfunctional mitochondria. This, in turn, exacerbates oxidative stress and energy deprivation in affected cells. Additionally, we have investigated the impact of Tau protein on mitophagy.

A crucial aspect of neurodegenerative disease research is the development of human models as essential tools for studying disease mechanisms. Several unmodified, patient-derived cell models have been shown to retain key pathological hallmarks observed in diseased brains. We have utilized peripheral cell models, such as fibroblasts, which exhibit mitophagy defects similar to those found in Alzheimer’s disease patients' brains. Furthermore, we have explored the olfactory mucosa as a direct source of neural cells and found that they retain characteristics observed in Amyotrophic Lateral Sclerosis (ALS), including motor neuron toxicity and inflammatory responses. Advances in cell reprogramming techniques have also allowed us to generate living neurons from other cell sources, such as fibroblasts and glial cells, providing a valuable model for studying neurodegenerative diseases in a brain-relevant cell type. We use neurons derived from induced pluripotent stem cells (iPSCs) to conduct functional assays on mitophagy alterations associated with familial Alzheimer’s disease linked to PSEN1 mutations.

Central nervous system (CNS) injuries remain an unresolved challenge in modern medicine. Identifying the mechanisms that prevent axonal regrowth and developing therapeutic solutions is one of our group’s main objectives. Cell therapy has emerged as a promising strategy for addressing this issue, and we have focused our efforts on two approaches. First, we investigate the use of olfactory ensheathing glia (OEG) to promote axonal regrowth. OEG is a specialized cell type with a natural ability to guide and support the growth of new olfactory sensory neuron axons as they connect to the appropriate targets in the olfactory bulb. These cells have been shown to induce axonal regrowth in vitro and to promote regeneration and functional recovery in spinal cord-injured animal models. Our research aims to identify the molecular and signaling pathways involved in OEG-mediated neuroregeneration, including factors such as matrix metalloproteinase-2 (MMP-2), brain-derived neurotrophic factor (BDNF), thrombin signaling, and plasminogen activator inhibitor-1 (PAI-1). Second, we explore the potential of reprogramming techniques to directly convert reactive astrocytes within the glial scar into functional neurons, thereby bypassing the injured area and restoring lost connections.

Past Lab Members, current employment

 

Students supervised by Dr. García-Escudero:

Supervision of Doctoral Theses:

  • Patricia Martín-Maestro Rojas
    Title: "Mitophagy Dysfunction in Peripheral and Neural Models of Alzheimer’s Disease."
    Department of Molecular Biology, Autonomous University of Madrid (2016).
  • Daniel Ruiz Gabarre
    Title: "Does the MAPT Gene Have Something New to Say? Discovery and Characterization of New Tau Protein Isoforms in Alzheimer’s Disease."
    Ph.D. in Neuroscience, Autonomous University of Madrid (2023).

Supervision of Six Undergraduate Theses in Human Nutrition and Dietetics (Autonomous University of Madrid, UAM):

  • 2022/2023 – Claudia Lozano Orcajo
    "Omega-3 Fatty Acids as a Neuroprotective Agent in Alzheimer’s Disease."
  • 2021/2022 – Marina Prieto Bercianos
    "Nutrition and Alzheimer’s Disease."
  • 2021/2022 – Alicia Peruca Santos
    "Implication of Epigenome Dynamics in Glioma Pathology and Its Potential Regulation Through Nutrition."
  • 2019/2020 – Víctor Valverde Salazar
    "Alzheimer’s and Green Tea: Epigallocatechin Gallate as a Neuroprotective Substance."
  • 2017/2018 – Paloma Fernández Sanz
    "Nutrition and Alzheimer’s Disease."
  • 2016/2017 – Joaquín García Cordero
    "Extra Virgin Olive Oil, Autophagy, and Alzheimer’s: Effects of Oleuropein Aglycone."
    Grade: Highest Honors. Awarded “Dietitian-Nutritionist Promise 2017” at the IV ADDINMA Conference.

Supervision of Seven Master’s Theses:

  • 2023/2024 – Anastasia Stoliarov Radushinskaya
    "Study of the Expression of Different Tau Isoforms in Exovesicle Secretion."
    Master’s in Neuroscience, UAM
  • 2022/2023 – Francisco Vallejo Bedia
    "Study of the Cellular Effects of Overexpressing New Tau Isoforms Generated by Intron Retention."
    Master’s in Neuroscience, Complutense University of Madrid
  • 2020/2021 – Almudena Carnero Espejo
    "Characterization of the Expression Mechanism and Function of New Truncated Tau Isoforms Generated by Intron Retention and Their Relevance in Alzheimer’s Disease."
    Master’s in Neuroscience, UAM
  • 2020/2021 – Marta Caamaño Moreno
    "Role of New Truncated Tau Protein Forms in Memory and Long-Term Synaptic Depression and Their Potential Relevance in Alzheimer’s Disease."
    Master’s in Neuroscience, UAM
  • 2020/2021 – Sara Ibáñez Santana
    "Effect of Truncated Tau Protein Isoforms on LTP and Conditioned Fear."
    Master’s in Neuroscience, UAM
  • 2018/2019 – Daniel Ruiz Gabarre
    "Functional Characterization of New Truncated Tau Isoforms in Alzheimer’s Disease Pathology."
    Highest Honors, Master’s in Neuroscience, UAM
  • 2017/2018 – Javier Pareja Román
    "Analysis of the Antitumoral Activity of Algernon, a Specific DYRK1A Inhibitor, in Gliomas."
    Master’s in Molecular Biosciences, UAM

 

 

Publications

REFERENCES

  • Portela-Lomba M, Simón D, Callejo-Móstoles M, de la Fuente G, Fernández de Sevilla D, García-Escudero V, Moreno-Flores MT, Sierra J. “Generation of functional neurons from adult human mucosal olfactory ensheathing glia by direct lineage conversión” (2024) Cell Death Dis. 15(7):478. doi: 10.1038/s41419-024-06862-9. 
  • Ruiz-Gabarre D, Valles-Saiz L, Carnero-Espejo A, Ferrer I, García-Escudero R, Hernández F, Ávila J, García-Escudero V. “Intron retention as a productive mechanism in human MAPT: RNA species generated by retention of intron 3” (2023) EBioMedicine. 2024 Feb;100:104953. doi: 10.1016/j.ebiom.2023.104953 
  • Valverde-Salazar V, Ruiz-Gabarre D, García-Escudero V. “Alzheimer's Disease and Green Tea: Epigallocatechin-3-Gallate as a Modulator of Inflammation and Oxidative Stress. Antioxidants (Basel). 2023 Jul 20;12(7):1460. doi: 10.3390/antiox12071460. 
  • Cuadros R, Pérez M, Ruiz-Gabarre D, Hernández F, García-Escudero V, Avila J. “Specific Peptide from the Novel W-Tau Isoform Inhibits Tau and Amyloid β Peptide Aggregation In Vitro”. (2022) ACS Chem Neurosci. 6;13(13):1974-1978. doi: 10.1021/acschemneuro.2c00188. 
  • Ruiz-Gabarre D, Carnero-Espejo A, Ávila J, García-Escudero V. “What's in a Gene? The Outstanding Diversity of MAPT”. (2022) Cells. 1;11(5):840. doi: 10.3390/cells11050840. Review. 
  • Perea JR, Bolós M, Cuadros R, García E, García-Escudero V, Hernández F, McManus RM, Heneka MT, Avila J. “p38 Inhibition Decreases Tau Toxicity in Microglia and Improves Their Phagocytic Function”. (2022) Mol Neurobiol. 59(3):1632-1648. doi: 10.1007/s12035-021-02715-0. 
  • Valles-Saiz L, Ruiz-Gabarre D, Garcia-Escudero V, Perry G, Avila J, Hernandez F. “Mouse and Human Tau Expression in Different Brain Areas” (2022) Journal of Alzheimer’s disease Reports. 6 (1):677-684.
  • García-Escudero V, Ruiz-Gabarre D, Gargini R, Pérez M, García E, Cuadros R, Hernández IH, Cabrera JR, García-Escudero R, Lucas JJ, Hernández F, Ávila J. (2021) Acta Neuropathol. Jul;142(1):159-177. doi: 10.1007/s00401-021-02317-z. 
  • Klionsky DJ, […], García-Escudero V, et al. “Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy (4th edition)”. (2021) Autophagy. Jan;17(1):1-382. doi: 10.1080/15548627.2020.1797280. 
  • Portela-Lomba M, Simón D, Russo C, Sierra J, Moreno-Flores MT. Coculture of Axotomized Rat Retinal Ganglion Neurons with Olfactory Ensheathing Glia, as an In Vitro Model of Adult Axonal Regeneration. J Vis Exp. 2020 Nov 2;(165). doi: 10.3791/61863. PMID: 33191937.
  • Gargini R, Segura-Collar B, Herránz B, García-Escudero V, Romero-Bravo A, Núñez FJ, García-Pérez D, Gutiérrez-Guamán J, Ayuso-Sacido A, Seoane J, Pérez-Núñez A, Sepúlveda-Sánchez JM, Hernández-Laín A, Castro MG, García-Escudero R, Ávila J, Sánchez-Gómez P. “The IDH-TAU-EGFR triad defines the neovascular landscape of diffuse gliomas”. (2020) Sci Transl Med. 12(527). pii: eaax1501.
  • Martín-Maestro P, Gargini R, García E, Simón D, Avila J, García-Escudero V. “Mitophagy Failure in APP and Tau Overexpression Model of Alzheimer's Disease”. (2019) J Alzheimers Dis. 70(2):525-540. 
  • Fernández-Sanz P, Ruiz-Gabarre D, García-Escudero V. “Modulating Effect of Diet on Alzheimer's Disease”. (2019) Diseases. 7(1). pii: E12. Review.
  • Ritter ML, Avila J, García-Escudero V, Hernández F, Pérez M. “Frontotemporal Dementia-Associated N279K Tau Mutation Localizes at the Nuclear Compartment”. Front Cell Neurosci. 2018; Jul 12;12:202. 
  • Pérez, M, Medina, M, Hernández, F and Avila, J.  "Secretion of full-length Tau or Tau fragments in cell culture models. Propagation of Tau in vivo and in vitro". Biomolecular Concepts 9.1 (2018): 1-11.
  • Cordero JC, García-Escudero R, Avila J, Gargini R, García-Escudero V. “Benefit of Oleuropein Aglycone for Alzheimer’s Disease by Promoting Autophagy”. Oxid Med Cell Longev. 2018; 2018:5010741. Review. 
  • Gómez RM, Sánchez MY, Portela-Lomba M, Ghotme K, Barreto GE, Sierra J, Moreno-Flores MT. "Cell therapy for spinal cord injury with olfactory ensheathing glia cells (OECs)". Glia 2018, Jan 13. doi: 10.1002/glia.23282. [Epub ahead of print] Review.
  • Martín-Maestro P, Gargini R, García E, Perry G, Avila J, García-Escudero V. “Slower Dynamics and Aged Mitochondria in Sporadic Alzheimer's Disease”. Oxid Med Cell Longev. 2017;2017:9302761. doi: 10.1155/2017/9302761. Epub 2017 Oct 19.
  • Martín-Maestro P, Gargini R, A Sproul A, García E, Antón LC, Noggle S, Arancio O, Avila J, García-Escudero V. “Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer's Disease-Associated Presenilin 1 Mutation”. Front Mol Neurosci. 2017 Sep 14;10:291. doi: 10.3389/fnmol.2017.00291. eCollection 2017.
  • García-Escudero V, Gargini R, Martín-Maestro P, García E, García-Escudero R, Avila J. “Tau mRNA 3'UTR-to-CDS ratio is increased in Alzheimer disease”. Neurosci Lett. 2017 Aug 10;655:101-108. doi: 10.1016/j.neulet.2017.07.007. Epub 2017 Jul 8.
  • Pérez M, Cuadros R, Hernández F, Avila J. “Secretion of full-length tau or tau fragments in a cell culture model”. Neurosci Lett. 2016 Nov 10; 634: 63-69.
  • Fu QQ, Wei L, Sierra J; Cheng JZ, Moreno-Flores MT, You H; Yu HR. “Olfactory Ensheathing Cell-Conditioned Medium Reverts Aβ25–35-Induced Oxidative Damage in SH-SY5Y Cells by Modulating the Mitochondria-Mediated Apoptotic Pathway”. Cell Mol Neurobiol. 2016 Nov 2. [Epub ahead of print].
  • Gargini R, García-Escudero V, Izquierdo M, Wandosell F. “Oncogene-mediated tumor transformation sensitizes cells to autophagy induction”. Oncol Rep. 2016 Jun; 35(6): 3689-95.
  • Martín-Maestro P, Gargini R, Perry G, Avila J, García-Escudero V. “PARK2 enhancement is able to compensate mitophagy alterations found in sporadic Alzheimer’s disease”. Hum Mol Genet. 2016 Feb 15;25(4):792-806.
  • Plaza N, Simón D, Sierra J, Moreno-Flores MT. “Transduction of an immortalized olfactory ensheathing glia cell line with the green fluorescent protein (GFP) gene: evaluation of its neuroregenerative capacity as a proof of concept”. Neurosci Lett 2016 Jan 26; 612: 25-31.
  • Reginensi D, Carulla P, Nocentini S, Seira O, Serra-Picamal X, Torres-Espín A, Matamoros-Angles A, Gavín R, Moreno-Flores MT, Wandosell F, Samitier J, Trepat X, Navarro X, Del Río JA. “Increased migration of olfactory ensheathing cells secreting the Nogo receptor ectodomain over inhibitory substrates and lesioned spinal cord”. Cell Mol Life Sci. 2015 Jul; 72: 2719-37.
  • García-Escudero V, Rosales M, Muñoz JL, Scola E, Medina J, Khalique H, Garaulet G, Rodriguez A, Lim F. “Patient-derived olfactory mucosa for study of the non-neuronal contribution to amyotrophic lateral sclerosis pathology.” J Cell Mol Med. 2015 Jun; 19(6): 1284-95.
  • Fernández-Montoya J, Pérez M. “Cathepsin D in a murine model of frontotemporal dementia with Parkinsonism-linked to chromosome 17”. Alzheimers Dis. 2015; 45(1):1-14.
  • Pérez M, Cuadros R, Pallas-Bazarra N, García C, Langa E, Jurado-Arjona J, Hernández F, Avila J. “Boronate-tau mediated uptake in neurons”. J Alzheimers Dis. 2014; 40(1): 143-51
  • de Cristóbal J, García-García L, Delgado M, Pérez M, Pozo MA, Medina M. “Longitudinal assessment of a transgenic animal model of tauopathy by FDG-PET imaging”. J Alzheimers Dis. 2014; 40 Suppl 1:S79-89.