Resumen: Background: In recent years, neuroglia has become a therapeutic target for neurodegenerative diseases. Despite the recognition of a variety of microglial morphologies associated with the neuroinflammatory process that involve diverse functionalities for this glial type, it is still unknown its beneficial or harmful role to the surrounding tissue. Methods: The study presented here proposes a novel approach to the neurodegenerative progression based on the reliability of its results due to the use of a natural model. Morphological alterations in microglia were assessed in cerebellar samples from prion-affected individuals at different stages of the natural disease (pre-clinical, clinical and terminal). Results: Immunohistochemical profiles confirmed that the abundance and morphology of the cells were found irrespective of the stage of the disease. Only an evident association of dystrophic pattern with advanced stages of the neurodegenerative process of scrapie was consistently demonstrated. Conclusions: Overall, we conclude that the observations described here support a potential failure of microglial cells that could perhaps lead to their inability to perform some of their physiological functions, maybe due to a senescent state. Gaining insight into the multifaceted roles of neuroglia in central nervous system (CNS) diseases is of critical importance in knowledge and understanding of CNS disease pathogenesis, but also in generating novel therapeutic strategies. Idioma: Inglés DOI: 10.31083/FBL47074 Año: 2025 Publicado en: Frontiers in Bioscience-Landmark 30, 10 (2025), 47074 [9 pp.] ISSN: 2768-6701 Financiación: info:eu-repo/grantAgreement/ES/UZ/2014-BIO-4 Tipo y forma: Artículo (Versión definitiva)