Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology.

Autor: Suelves N; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium., Saleki S; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium., Ibrahim T; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium., Palomares D; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium., Moonen S; Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.; Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.; Vlaams Instituut Voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium., Koper MJ; Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.; Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.; Vlaams Instituut Voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium., Vrancx C; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium.; Laboratory for Membrane Trafficking, Department of Neurosciences, Vlaams Instituut Voor Biotechnologie (VIB) Center for Brain and Disease Research, KU Leuven, Leuven, Belgium., Vadukul DM; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium.; Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, London, UK., Papadopoulos N; Ludwig Institute for Cancer Research, Brussels, Belgium.; SIGN Unit, de Duve Institute, UCLouvain, Brussels, Belgium., Viceconte N; Genetic and Epigenetic Alterations of Genomes Unit, de Duve Institute, UCLouvain, Brussels, Belgium.; CENTOGENE GmbH, 18055, Rostock, Germany., Claude E; Genetic and Epigenetic Alterations of Genomes Unit, de Duve Institute, UCLouvain, Brussels, Belgium., Vandenberghe R; Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium.; Department of Neurology, University Hospital Leuven, Leuven, Belgium., von Arnim CAF; Department of Neurology, University of Ulm, Ulm, Germany.; Department of Geriatrics, University Medical Center Göttingen, Göttingen, Germany., Constantinescu SN; Ludwig Institute for Cancer Research, Brussels, Belgium.; SIGN Unit, de Duve Institute, UCLouvain, Brussels, Belgium.; Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Brussels, Belgium.; Nuffield Department of Medicine, Ludwig Institute for Cancer Research, Oxford University, Oxford, UK., Thal DR; Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium.; Department of Pathology, University Hospital Leuven, Leuven, Belgium., Decottignies A; Genetic and Epigenetic Alterations of Genomes Unit, de Duve Institute, UCLouvain, Brussels, Belgium., Kienlen-Campard P; Aging and Dementia Group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium. pascal.kienlen-campard@uclouvain.be.
Jazyk: angličtina
Zdroj: Acta neuropathologica communications [Acta Neuropathol Commun] 2023 May 17; Vol. 11 (1), pp. 82. Date of Electronic Publication: 2023 May 17.
DOI: 10.1186/s40478-023-01578-x
Abstrakt: Aging is the main risk factor for Alzheimer's disease (AD) and other neurodegenerative pathologies, but the molecular and cellular changes underlying pathological aging of the nervous system are poorly understood. AD pathology seems to correlate with the appearance of cells that become senescent due to the progressive accumulation of cellular insults causing DNA damage. Senescence has also been shown to reduce the autophagic flux, a mechanism involved in clearing damaged proteins from the cell, and such impairment has been linked to AD pathogenesis. In this study, we investigated the role of cellular senescence on AD pathology by crossing a mouse model of AD-like amyloid-β (Aβ) pathology (5xFAD) with a mouse model of senescence that is genetically deficient for the RNA component of the telomerase (Terc -/- ). We studied changes in amyloid pathology, neurodegeneration, and the autophagy process in brain tissue samples and primary cultures derived from these mice by complementary biochemical and immunostaining approaches. Postmortem human brain samples were also processed to evaluate autophagy defects in AD patients. Our results show that accelerated senescence produces an early accumulation of intraneuronal Aβ in the subiculum and cortical layer V of 5xFAD mice. This correlates with a reduction in amyloid plaques and Aβ levels in connecting brain regions at a later disease stage. Neuronal loss was specifically observed in brain regions presenting intraneuronal Aβ and was linked to telomere attrition. Our results indicate that senescence affects intraneuronal Aβ accumulation by impairing autophagy function and that early autophagy defects can be found in the brains of AD patients. Together, these findings demonstrate the instrumental role of senescence in intraneuronal Aβ accumulation, which represents a key event in AD pathophysiology, and emphasize the correlation between the initial stages of amyloid pathology and defects in the autophagy flux.
(© 2023. The Author(s).)
Databáze: MEDLINE
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