Downregulation of forkhead box O1 (FOXO1) acetylation ameliorates cognitive dysfunction by inhibiting endoplasmic reticulum stress‐regulated neuronal apoptosis in APP/PS1 transgenic mice
Authors: Zhang Nan , Zhao Zongyuan , Chen Xiaoxiao , Yao Hanbing , Zhu Min , Ma Shuqing , Wang Hui , Yin Xianghong , Zhou Ying , Zheng Chenfei , Li Jianmin , Pan Jingye , Wang Kaicheng , Yang Bin , Wang Yunting , Fan Junming , Gong Yongsheng , Liu Rong , Zeng Jing , Fan Xiaofang , Shentu Yangping 
Published: February 2025

AbstractBackgroundAlzheimer's disease (AD) is a neurodegenerative disorder that affects the central nervous system. Silent information regulator sirtuin 1 (SIRT1) may deacetylate and suppress forkhead box O (FOXO) activities to promote neuronal survival. FOXO1 is involved in the regulation of metabolism, senescence, stress response, and apoptosis. Moreover, endoplasmic reticulum stress (ERS) mediates cell apoptosis. Therefore, this study aimed to determine whether the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS‐mediated apoptosis in amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice.MethodsWe used APP/PS1 transgenic mice to construct an in vivo AD model. Additionally, we used β‐amyloid (Aβ)‐incubated HT22 cells and primary neurons (PNs) for in vitro analyses. Cognitive function was assessed using novel object recognition, the Morris water maze, and fear conditioning. Discrepancies between wild‐type (WT) and APP/PS1 transgenic mice were evaluated using an unpaired t test. In addition, one‐way analysis of variance was conducted for behavioral assessments and other tests involving four distinct groups, followed by a Tukey's honestly significant difference test for post hoc pairwise comparisons.ResultsThe expression of SIRT1 was downregulated (in animal experiments, WT mice vs. APP/PS1 mice, n = 3, p = 0.002; in cell experiments, HT22 cells vs. HT22 cells + Aβ1–42, n = 3, p = 0.001; primary neurons vs. primary neurons + Aβ1−42, n = 3, p < 0.001), whereas FOXO1 acetylation was upregulated both in vivo and in vitro (in animal experiments, WT mice vs. APP/PS1 mice, n = 3, p < 0.001; in cell experiments, HT22 cells vs. HT22 cells + Aβ1−42, n = 3, p = 0.004; primary neurons vs. primary neurons + Aβ1–42, n = 3, p < 0.001), leading to cognitive dysfunction, Aβ plaque deposition, and neuronal apoptosis. Quercetin, a SIRT1 agonist, reversed these changes (For SIRT1, APP/PS1 mice vs. Quercetin‐treated APP/PS1 mice, n = 3, p = 0.014; HT22 cells + Aβ1−42 vs. HT22 cells + Aβ1−42 + Quercetin, n = 3, p = 0.003; primary neurons + Aβ1−42 vs. primary neurons + Aβ1−42 + Quercetin, n = 3, p = 0.014. For ac‐FOXO1, APP/PS1 mice vs. Quercetin‐treated APP/PS1 mice, n = 3, p < 0.001; HT22 cells+ Aβ1−42 vs. HT22 cells + Aβ1−42 + Quercetin, n = 3, p = 0.023; primary neurons + Aβ1−42 vs. primary neurons + Aβ1−42 + Quercetin, n = 3, p = 0.003). However, the FOXO1 antagonist AS1842856 invalidated the positive effects of quercetin in APP/PS1 transgenic mice (ac‐FOXO1: Quercetin‐treated APP/PS1 mice vs. AS1842856‐treated APP/PS1 mice, n = 3, p < 0.001). Quercetin counteracted FOXO1 acetylation and ERS‐mediated apoptosis. In contrast, AS1842856 promoted these processes in vivo and in vitro.ConclusionOur findings demonstrate that the downregulation of SIRT1 expression exacerbates cognitive dysfunction by activating FOXO1 acetylation and promoting ERS‐mediated apoptosis.