Researchers from the Universidad Autónoma de Madrid (UAM) and the Hospital Universitari de Bellvitge in Barcelona have discovered a spontaneous response of the brain of adult rats after stroke that facilitates neurological and motor recovery. The study reveals an increase in oligodendrocytes that promotes remyelination of damaged tissue. Understanding this process opens new avenues to develop effective treatments against cerebral ischemia.
Researchers from the Department of Biology of the Faculty of Sciences of the Autonomous University of Madrid (UAM), belonging to the Neurodegeneration and cerebral ischemia research group, in collaboration with the Department of Pathology of the Hospital Universitari de Bellvitge, have identified a spontaneous response of the brain of adult rats after a stroke, which allows the neurological and motor recovery of affected individuals.
The discovery, published in Molecular Basis of Disease, opens the door to new therapeutic targets that could significantly improve the recovery of stroke patients.
When cerebral ischemia or stroke occurs, an increase in oligodendrocyte precursors (OPCs) is observed in the affected brain region. Over time, these precursors differentiate into pre-myelinating oligodendrocytes and finally into mature oligodendrocytes, which are capable of myelinating axons. This increase in mature oligodendrocytes is associated with remyelination of stroke-affected tissue, resulting in the recovery of certain brain functions.
After cerebral ischemia, oligodendrocytes located in the damaged tissue show elevated levels of the 3R isoform of the Tau protein (3RTau), which is crucial during embryonic development of the central nervous system and is related to a more dynamic microtubule cytoskeleton. The expression of this isoform in the adult brain after ischemia, specifically in pre-myelinating oligodendrocytes, suggests that it could play a key role in their differentiation and subsequent remyelination of brain tissue.
However, in human brain tissue samples obtained from patients who have died of stroke, this phenomenon has not been observed: neither an increase in oligodendrocytes nor an increase in 3RTau protein. This suggests that the mechanism identified in rats could be essential for the recovery of the affected tissue.
"Understanding in detail the molecular mechanism that increases 3RTau protein in oligodendrocytes could be fundamental to design therapies that reduce the devastating consequences of cerebral ischemia in patients, as well as the high socioeconomic impact of this disease," the authors note.
To conduct the study, the investigators used the "permanent middle cerebral artery occlusion" (pMCAO) in vivo model of cerebral ischemia. This procedure involves the permanent insertion of a suture at the base of the middle cerebral artery (MCA) for the duration of the study, simulating cases where the occlusion remains indefinitely.
Brain and myelin analysis
For the analysis of the brain and myelin, the scientists used different techniques, such as Nissl staining, to identify the histological state of the tissue; immunofluorescence and confocal microscopy, to study oligodendrocyte populations and 3RTau protein expression; Black Gold II staining, to assess the general state of myelin; Western Blot, to quantify specific myelin proteins; and transmission electron microscopy, to analyze the ultrastructure of myelin and its state of compaction.
In addition, they performed primary cultures of oligodendrocytes at different stages of differentiation to demonstrate the specific presence of 3RTau protein in oligodendrocytes.
Thus, the authors demonstrated, for the first time, that, in the long term, after cerebral ischemia, a process of spontaneous remyelination occurs that counteracts the loss of myelin caused by ischemic damage.
"Unlike many previous studies that focused on the effects on neurons in the acute phase of the disease, using transient stroke models, this model of permanent ischemia simulates cases in which the arterial blockage is not eliminated and prolongs ischemia for up to 21 days, allowing the long-term brain response to be observed. This is crucial, as a large number of patients cannot receive immediate treatment," the authors conclude.
Bibliographic reference:
Gerardo Martín-Lopez, Paula R. Mallavibarrena, Mario Villa-Gonzalez, Noemi Vidal, Maria José Pérez-Alvarez, 2024, "The dynamics of oligodendrocyte populations following permanent ischemia promotes long-term spontaneous remyelination of damaged area, Biochimica et Biophysica Acta (BBA)", Molecular Basis of Disease, Volume 1870, Issue 7,167270,ISSN 0925-4439. https://doi.org/10.1016/j.bbadis.2024.167270
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