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

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 (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)
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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.

Original languageEnglish
Article numbere13814
Number of pages18
JournalAging Cell
Volume22
Issue number5
Early online date27 Mar 2023
DOIs
Publication statusPublished - May 2023

Keywords

  • aging
  • axon pathology
  • cognition
  • hippocampus
  • memory
  • necroptosis
  • rejuvenation
  • synaptic transmission

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