Necroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation.

Autor: Arrázola MS; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile., Lira M; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Véliz-Valverde F; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile., Quiroz G; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile., Iqbal S; The Roslin Institute, University of Edinburgh, Edinburgh, UK.; Massive Analytic Ltd., London, UK., Eaton SL; The Roslin Institute, University of Edinburgh, Edinburgh, UK., Lamont DJ; FingerPrints Proteomics Facility, School of Life Sciences, University of Dundee, Dundee, UK., Huerta H; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile., Ureta G; Fundación Ciencia & Vida, Santiago, Chile., Bernales S; Fundación Ciencia & Vida, Santiago, Chile., Cárdenas JC; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.; Buck Institute for Research on Aging, Novato, California, USA.; Department of Chemistry and Biochemistry, University of California, Santa Barbara, California, USA., Cerpa W; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile., Wishart TM; The Roslin Institute, University of Edinburgh, Edinburgh, UK., Court FA; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.; Buck Institute for Research on Aging, Novato, California, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2023 May; Vol. 22 (5), pp. e13814. Date of Electronic Publication: 2023 Mar 27.
DOI: 10.1111/acel.13814
Abstrakt: 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.
(© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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