Glial Cells and Myelin as Therapeutic Targets in Aging and Neurodegenerative Diseases
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KEYWORDS
Myelin
Human samples
Alzheimer's disease
Multiple sclerosis
Neuroimmflamation
Glia
TECHNIQUES
Brain organoids
iPSCs and reprogramming
Transcriptomics
Histochemistry
Electrophysiology
Multiple electrode arrays
EAE
Overall scope
The progressive aging of the population in the developed world and its sedentary habits have led to a dramatic increase in neurodegenerative diseases, the main risk factor of which is age. Despite this, effective treatments have not been developed to alleviate the neurological deterioration caused by these diseases due to the limited understanding we have of their pathophysiology. Furthermore, demyelinating diseases become chronic and produce progressive neurodegeneration due to the lack of drugs that promote myelin repair.
All of these diseases present with tissue damage in the gray and white matter of the brain and are accompanied by the loss of neurons and glia, and alterations in signaling between both cell groups. Our laboratory has been investigating the role of glial cells in the healthy brain for over 25 years, as well as their alterations in the etiopathogenesis of multiple sclerosis and Alzheimer's and Parkinson's diseases. To do this, we use mouse and human cell models, as well as postmortem samples of human nervous tissue and biological samples from living patients affected by these diseases. In these studies, we apply a wide range of techniques encompassing cellular and molecular biology, genetics, biochemistry, histology, and electrophysiology. The overall objective of the project is to identify and characterize new glial molecular targets that mediate damage to the central nervous system and to determine the experimental conditions under which it is attenuated. The definition of these targets will serve to develop new therapeutic strategies with drugs that slow the progression of these diseases and improve patients' quality of life.
Funded by CIBERNED and Basque Government.
Combined Neuroprotective Therapies to Halt Multiple Sclerosis
The hallmark of multiple sclerosis (MS) is progressive demyelination together with oligodendrocyte damage and ensuing neurodegeneration. Myelin loss in plaques in remitting-relapsing, or/and diffusely in progressive MS results in neurological deterioration due to a slowdown in impulse propagation, shortage of energy supply along the myelin-axon unit, and ultimately axonal damage and Wallerian degeneration.
Currently, clinicians are endowed with a large arsenal of immunomodulatory disease-modifying drugs that attenuate symptoms and delay the course of relapsing-remitting MS, but fail to halt progressive MS. As oligodendrocyte/myelin damage accumulates early on MS pathophysiology, we hypothesize that combined treatment with myelin protectors and boosters is an effective manner to stop MS progression. Accordingly, STOP-MS project proposes to challenge this idea by co-administering both types of drugs to promote remyelination of demyelinated regions while preserving oligodendrocytes and myelin in healthy tissue.
STOP-MS is a proof-of-concept project aiming at finding the most effective combination of myelin protectors and boosters. To that end, we will exploit the neurotransmitter signalling machinery of oligodendrocytes and myelin together with drugs that promote myelin lipid catabolism and myelin-derived fatty acid synthesis.
STOP-MS is a multidisciplinary project that has four major objectives:
1- Drug screening in 2D co-cultures of human iPSCs-derived neurons and oligodendrocytes from healthy subjects and MS patients.
2- Validation of in vitro findings, in both inflammatory and non-inflammatory mouse models of MS in vivo using PET and MRI, neurophysiology and immunochemistry.
3- Pre-design of clinical trials to assay drugs in progressive MS patients.
The results of STOP-MS will lead to novel therapeutic strategies ready to test in clinical trials, that will dramatically improve progressive MS prognosis.
Funded by EITB-Maratoia, Basque Government and MICINN of Spanish Government.
Human cortical organoids to study Alzheimer´s disease
Human brain organoids have ushered in a new era for modeling neurodegenerative diseases. Our research focuses on elucidating the role of oligodendrocytes and myelin in the onset and progression of Alzheimer’s disease (AD). We hypothesize that age-related myelin dysfunction impairs neural connectivity and disrupts metabolic support to neurons and glia, thereby contributing to AD pathogenesis. Challenging conventional views, we propose that restoring myelin integrity, modulating myelin lipid catabolism, or supplementing myelin-derived fatty acids may mitigate neuropathological features and functional deficits in AD. To investigate this, we generate cortical organoids from induced pluripotent stem cells (iPSCs) derived from patients with both sporadic and familial forms of AD. These organoids recapitulate key hallmarks of AD pathology, which we analyze using high-resolution microscopy, immunohistochemistry, and electrophysiology. Preliminary findings indicate that myelin-derived fatty acids can partially reverse AD-associated pathology.
Funded by EiTB Maratoia.
Organoid from human neural stem cells recapitulating brain development
Publications related to this topic
López-Muguruza E, Peiró-Moreno C, Ruiz A, Matute C. Oligodendrocyte and Myelin Pathophysiology in Multiple Sclerosis. Adv Neurobiol. 2025;43:317-361. doi: 10.1007/978-3-031-87919-7_12. PMID: 40500503.
López-Muguruza E, Peiró-Moreno C, Pérez-Cerdá F, Matute C, Ruiz A. Del Río Hortega's insights into oligodendrocytes: recent advances in subtype characterization and functional roles in axonal support and disease. Front Neuroanat. 2025 Mar 12;19:1557214. doi: 10.3389/fnana.2025.1557214. PMID: 40145026; PMCID: PMC11936973.
Montilla A, Zabala A, Calvo I, Bosch-Juan M, Tomé-Velasco I, Mata P, Koster M, Sierra A, Kooistra SM, Soria FN, Eggen BJL, Fresnedo O, Fernández JA, Tepavcevic V, Matute C, Domercq M. Microglia regulate myelin clearance and cholesterol metabolism after demyelination via interferon regulatory factor 5. Cell Mol Life Sci. 2025 Mar 26;82(1):131. doi: 10.1007/s00018-025-05648-2. PMID: 40137979; PMCID: PMC11947375.
Moreno-García A, Serrat R, Julio-Kalajzic F, Bernal-Chico A, Baraibar AM, Matute C, Marsicano G, Mato S. In Vivo Assessment of Cortical Astrocyte Network Dysfunction During Autoimmune Demyelination: Correlation With Disease Severity. J Neurochem. 2025 Feb;169(2):e16305. doi: 10.1111/jnc.16305. PMID: 39957272.
Maudes E, Planagumà J, Marmolejo L, Radosevic M, Serafim AB, Aguilar E, Sindreu C, Landa J, García-Serra A, Mannara F, Cunquero M, Smit A, Milano C, Peixoto-Moledo P, Guasp M, Ruiz-García R, Gray SM, Spatola M, Loza-Alvarez P, Sabater L, Matute C, Dalmau J. Neuro-immunobiology and treatment assessment in a mouse model of anti-NMDAR encephalitis. Brain. 2025 Jun 3;148(6):2023-2037. doi: 10.1093/brain/awae410. PMID: 39719005.
Sánchez de la Torre A, Ezquerro-Herce S, Huerga-Gómez A, Sánchez-Martín E, Chara JC, Matute C, Monory K, Mato S, Lutz B, Guzmán M, Aguado T, Palazuelos J. CB<sub>1</sub> receptors in NG2 cells mediate cannabinoid-evoked functional myelin regeneration. Prog Neurobiol. 2024 Dec;243:102683. doi: 10.1016/j.pneurobio.2024.102683. Epub 2024 Nov 9. PMID: 39528076.
Dematteis G, Tapella L, Casali C, Talmon M, Tonelli E, Reano S, Ariotti A, Pessolano E, Malecka J, Chrostek G, Kulkovienė G, Umbrasas D, Distasi C, Grilli M, Ladds G, Filigheddu N, Fresu LG, Mikoshiba K, Matute C, Ramos-Gonzalez P, Jekabsone A, Calì T, Brini M, Biggiogera M, Cavaliere F, Miggiano R, Genazzani AA, Lim D. ER-mitochondria distance is a critical parameter for efficient mitochondrial Ca<sup>2+</sup> uptake and oxidative metabolism. Commun Biol. 2024 Oct 10;7(1):1294. doi: 10.1038/s42003-024-06933-9. PMID: 39390051; PMCID: PMC11467464.
Baraibar AM, Colomer T, Moreno-García A, Bernal-Chico A, Sánchez-Martín E, Utrilla C, Serrat R, Soria-Gómez E, Rodríguez-Antigüedad A, Araque A, Matute C, Marsicano G, Mato S. Autoimmune inflammation triggers aberrant astrocytic calcium signaling to impair synaptic plasticity. Brain Behav Immun. 2024 Oct;121:192-210. doi: 10.1016/j.bbi.2024.07.010. Epub 2024 Jul 18. PMID: 39032542; PMCID: PMC11415231.
Sainz A, Pérez F, Pérez-Samartín A, Panicker M, Ruiz A, Matute C. Pros and Cons of Human Brain Organoids to Study Alzheimer's Disease. Aging Dis. 2025 Jan 9. doi: 10.14336/AD.2024.1409. Epub ahead of print. PMID: 39812548.
Bonifazi G, Luchena C, Gaminde-Blasco A, Ortiz-Sanz C, Capetillo-Zarate E, Matute C, Alberdi E, De Pittà M. A nonlinear meccano for Alzheimer's emergence by amyloid β-mediated glutamatergic hyperactivity. Neurobiol Dis. 2024 May;194:106473. doi: 10.1016/j.nbd.2024.106473. Epub 2024 Mar 15. PMID: 38493903.
López-Muguruza E, Matute C. Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis. Int J Mol Sci. 2023 Aug 18;24(16):12912. doi: 10.3390/ijms241612912. PMID: 37629092; PMCID: PMC10454078.
Alanko V, Gaminde-Blasco A, Quintela-López T, Loera-Valencia R, Solomon A, Björkhem I, Cedazo-Minguez A, Maioli S, Tabacaru G, Latorre-Leal M, Matute C, Kivipelto M, Alberdi E, Sandebring-Matton A. 27-hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia-associated brain white matter changes. Glia. 2023 Jun;71(6):1414-1428. doi: 10.1002/glia.24348. Epub 2023 Feb 13. PMID: 36779429.
Montilla A, Zabala A, Er-Lukowiak M, Rissiek B, Magnus T, Rodriguez-Iglesias N, Sierra A, Matute C, Domercq M. Microglia and meningeal macrophages depletion delays the onset of experimental autoimmune encephalomyelitis. Cell Death Dis. 2023 Jan 12;14(1):16. doi: 10.1038/s41419-023-05551-3. PMID: 36635255; PMCID: PMC9835747.
Manterola A, Chara JC, Aguado T, Palazuelos J, Matute C, Mato S. Cannabinoid CB<sub>1</sub> receptor expression in oligodendrocyte progenitors of the hippocampus revealed by the NG2-EYFP-knockin mouse. Front Neuroanat. 2022 Oct 28;16:1030060. doi: 10.3389/fnana.2022.1030060. PMID: 36387996; PMCID: PMC9650068.
Serrano-Regal MP, Bayón-Cordero L, Chara Ventura JC, Ochoa-Bueno BI, Tepavcevic V, Matute C, Sánchez-Gómez MV. GABA<sub>B</sub> receptor agonist baclofen promotes central nervous system remyelination. Glia. 2022 Dec;70(12):2426-2440. doi: 10.1002/glia.24262. Epub 2022 Aug 18. PMID: 35980256; PMCID: PMC9804779.
Bayón-Cordero L, Ochoa-Bueno BI, Ruiz A, Ozalla M, Matute C, Sánchez-Gómez MV. GABA Receptor Agonists Protect From Excitotoxic Damage Induced by AMPA in Oligodendrocytes. Front Pharmacol. 2022 Jul 26;13:897056. doi: 10.3389/fphar.2022.897056. PMID: 35959434; PMCID: PMC9360600.
Akwa Y, Di Malta C, Zallo F, Gondard E, Lunati A, Diaz-de-Grenu LZ, Zampelli A, Boiret A, Santamaria S, Martinez-Preciado M, Cortese K, Kordower JH, Matute C, Lozano AM, Capetillo-Zarate E, Vaccari T, Settembre C, Baulieu EE, Tampellini D. Stimulation of synaptic activity promotes TFEB-mediated clearance of pathological MAPT/Tau in cellular and mouse models of tauopathies. Autophagy. 2023 Feb;19(2):660-677. doi: 10.1080/15548627.2022.2095791. Epub 2022 Jul 22. PMID: 35867714; PMCID: PMC9851246.
Aigrot MS, Barthelemy C, Moyon S, Dufayet-Chaffaud G, Izagirre-Urizar L, Gillet-Legrand B, Tada S, Bayón-Cordero L, Chara JC, Matute C, Cartier N, Lubetzki C, Tepavčević V. Genetically modified macrophages accelerate myelin repair. EMBO Mol Med. 2022 Aug 8;14(8):e14759. doi: 10.15252/emmm.202114759. Epub 2022 Jul 13. PMID: 5822550; PMCID: PMC9358396.
Sánchez-de la Torre A, Aguado T, Huerga-Gómez A, Santamaría S, Gentile A, Chara JC, Matute C, Monory K, Mato S, Guzmán M, Lutz B, Galve-Roperh I, Palazuelos J. Cannabinoid CB<sub>1</sub> receptor gene inactivation in oligodendrocyte precursors disrupts oligodendrogenesis and myelination in mice. Cell Death Dis. 2022 Jul 7;13(7):585. doi: 10.1038/s41419-022-05032-z. PMID: 35798697; PMCID: PMC9263142.
Fernandez-Alvarez M, Atienza M, Zallo F, Matute C, Capetillo-Zarate E, Cantero JL. Linking Plasma Amyloid Beta and Neurofilament Light Chain to Intracortical Myelin Content in Cognitively Normal Older Adults. Front Aging Neurosci. 2022 Jun 17;14:896848. doi: 10.3389/fnagi.2022.896848. PMID: 35783126; PMCID: PMC9247578.
Ortiz-Sanz C, Llavero F, Zuazo-Ibarra J, Balantzategi U, Quintela-López T, Wyssenbach A, Capetillo-Zarate E, Matute C, Alberdi E, Zugaza JL. Recombinant Integrin β1 Signal Peptide Blocks Gliosis Induced by Aβ Oligomers. Int J Mol Sci. 2022 May 20;23(10):5747. doi: 10.3390/ijms23105747. PMID: 35628557; PMCID: PMC9146559.
Luchena C, Zuazo-Ibarra J, Valero J, Matute C, Alberdi E, Capetillo-Zarate E. A Neuron, Microglia, and Astrocyte Triple Co-culture Model to Study Alzheimer's Disease. Front Aging Neurosci. 2022 Apr 14;14:844534. doi: 10.3389/fnagi.2022.844534. PMID: 35493929; PMCID: PMC9048896.
Palma A, Chara JC, Montilla A, Otxoa-de-Amezaga A, Ruíz-Jaén F, Planas AM, Matute C, Pérez-Samartín A, Domercq M. Clemastine Induces an Impairment in Developmental Myelination. Front Cell Dev Biol. 2022 Mar 17;10:841548. doi: 10.3389/fcell.2022.841548. PMID: 35372341; PMCID: PMC8970281.
Bernal-Chico A, Tepavcevic V, Manterola A, Utrilla C, Matute C, Mato S. Endocannabinoid signaling in brain diseases: Emerging relevance of glial cells. Glia. 2023 Jan;71(1):103-126. doi: 10.1002/glia.24172. Epub 2022 Mar 30. PMID: 35353392; PMCID: PMC9790551.
Ortiz-Sanz C, Balantzategi U, Quintela-López T, Ruiz A, Luchena C, Zuazo- Ibarra J, Capetillo-Zarate E, Matute C, Zugaza JL, Alberdi E. Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease. Cell Death Dis. 2022 Mar 19;13(3):253. doi: 10.1038/s41419-022-04687-y. PMID: 35306512; PMCID: PMC8934345.
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