Abstract Dysregulation of the nucleolus and its associated protein synthesis machinery is implicated as a contributing factor in the progressive neuronal atrophy observed in Alzheimer's disease (AD). This study investigated the neuroprotective effects of icariin (ICA) via modulation of the nucleolar stress response in Aβ 25–35 -treated BV2 cells and APP/PS1 transgenic mice. Cell viability and morphological alterations were evaluated using flow cytometry, microscopic observation, and CCK-8 assays, while cognitive function in mice was assessed with the morris water maze test. BV2 cells and mouse hippocampal tissues were further analyzed for rRNA transcription, rDNA methylation status, nucleolar morphology, and the expression of nucleolar proteins ribosomal protein L5 (RPL5) and RPL11, as well as mouse double minutes 2 (MDM2) and p53. Aβ 25–35 exposure induced significant reductions of cell viability and morphological abnormalities in BV2 cells, whereas APP/PS1 mice exhibited marked cognitive deficits. Both in vitro and in vivo models demonstrated pronounced nucleolar stress, characterized by reduced pre-rRNA transcription, hypermethylation of the rDNA promoter, decreased nucleolar number and volume, and upregulated expressions of RPL5, RPL11, MDM2, and p53. Further ICA administration reversed the morphological changes and increased the cell viability in Aβ 25–35 -treated BV2 cells, and alleviated the cognitive defects in APP/PS1 mice. More importantly, ICA treatment showed strong protective effects on suppressing the nucleolar stress response in both in vivo and in vitro AD models. Collectively, these findings highlight nucleolar stress modulation as a potential therapeutic target in AD and support ICA as a promising natural candidate for intervention.
Zheng et al. (Wed,) studied this question.