AUTHOR=Lu Donglei , Zhang Wenyu , Li Ruiyu , Tan Sijie , Zhang Yan 

TITLE=Targeting necroptosis in Alzheimer’s disease: can exercise modulate neuronal death?

JOURNAL=Frontiers in Aging Neuroscience

VOLUME=Volume 17 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2025.1499871

DOI=10.3389/fnagi.2025.1499871

ISSN=1663-4365

ABSTRACT=Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive decline and neuronal degeneration. Emerging evidence implicates necroptosis in AD pathogenesis, driven by the RIPK1-RIPK3-MLKL pathway, which promotes neuronal damage, inflammation, and disease progression. Exercise, as a non-pharmacological intervention, can modulate key inflammatory mediators such as TNF-α, HMGB1, and IL-1β, thereby inhibiting necroptotic signaling. Additionally, exercise enhances O-GlcNAc glycosylation, preventing Tau hyperphosphorylation and stabilizing neuronal integrity. This review explores how exercise mitigates necroptosis and neuroinflammation, offering novel therapeutic perspectives for AD prevention and management.