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

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dc.contributor.authorArrazola, Macarena S.
dc.contributor.authorLira, Matias
dc.contributor.authorVeliz-Valverde, Felipe
dc.contributor.authorQuiroz, Gabriel
dc.contributor.authorIqbal, Somya
dc.contributor.authorEaton, Samantha L.
dc.contributor.authorLamont, Douglas J.
dc.contributor.authorHuerta, Hernan
dc.contributor.authorUreta, Gonzalo
dc.contributor.authorBernales, Sebastian
dc.contributor.authorCardenas, J. Cesar
dc.contributor.authorCerpa, Waldo
dc.contributor.authorWishart, Thomas M.
dc.contributor.authorCourt, Felipe A.
dc.date.accessioned2025-01-20T20:15:57Z
dc.date.available2025-01-20T20:15:57Z
dc.date.issued2023
dc.description.abstractAge 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.
dc.fuente.origenWOS
dc.identifier.doi10.1111/acel.13814
dc.identifier.eissn1474-9726
dc.identifier.issn1474-9718
dc.identifier.urihttps://doi.org/10.1111/acel.13814
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92295
dc.identifier.wosidWOS:000959295200001
dc.issue.numero5
dc.language.isoen
dc.revistaAging cell
dc.rightsacceso restringido
dc.subjectaging
dc.subjectaxon pathology
dc.subjectcognition
dc.subjecthippocampus
dc.subjectmemory
dc.subjectnecroptosis
dc.subjectrejuvenation
dc.subjectsynaptic transmission
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleNecroptosis inhibition counteracts neurodegeneration, memory decline, and key hallmarks of aging, promoting brain rejuvenation
dc.typeartículo
dc.volumen22
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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