Icariin targets p53 to protect against ceramide-induced neuronal senescence: Implication in Alzheimer's disease

Background Alzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood. Aim In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects. Methods We pretreated HT-22?cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, β-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin. Results Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection. Conclusion Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.

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