Necroptosis inhibition counteracts neurodegeneration,memory decline,and key hallmarks of aging,promoting brain rejuvenation |
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Authors: | Macarena S Arrázola Matías Lira Felipe Véliz-Valverde Gabriel Quiroz Somya Iqbal Samantha L Eaton Douglas J Lamont Hernán Huerta Gonzalo Ureta Sebastián Bernales J César Cárdenas Waldo Cerpa Thomas M Wishart Felipe A Court |
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Institution: | 1. Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile;2. Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile;3. Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile;4. The Roslin Institute, University of Edinburgh, Edinburgh, UK;5. FingerPrints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK;6. Fundación Ciencia & Vida, Santiago, Chile |
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Abstract: | Age is the main risk factor for the development of neurodegenerative diseases. In the aged brain, axonal degeneration is an early pathological event, preceding neuronal dysfunction, and cognitive disabilities in humans, primates, rodents, and invertebrates. Necroptosis mediates degeneration of injured axons, but whether necroptosis triggers neurodegeneration and cognitive impairment along aging is unknown. Here, we show that the loss of the necroptotic effector Mlkl was sufficient to delay age-associated axonal degeneration and neuroinflammation, protecting against decreased synaptic transmission and memory decline in aged mice. Moreover, short-term pharmacologic inhibition of necroptosis targeting RIPK3 in aged mice, reverted structural and functional hippocampal impairment, both at the electrophysiological and behavioral level. Finally, a quantitative proteomic analysis revealed that necroptosis inhibition leads to an overall improvement of the aged hippocampal proteome, including a subclass of molecular biofunctions associated with brain rejuvenation, such as long-term potentiation and synaptic plasticity. Our results demonstrate that necroptosis contributes to age-dependent brain degeneration, disturbing hippocampal neuronal connectivity, and cognitive function. Therefore, necroptosis inhibition constitutes a potential geroprotective strategy to treat age-related disabilities associated with memory impairment and cognitive decline. |
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Keywords: | aging axon pathology cognition hippocampus memory necroptosis rejuvenation synaptic transmission |
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