The gut–brain axis is currently being studied as a therapeutic strategy for neurological diseases, especially Alzheimer’s disease (AD). Obesity results in the gut microbiota dysbiosis, which includes butyrate-producing bacteria are reduced. Although sodium butyrate (NaB) has emerged as the potential therapeutic substance in AD, there is a lack of detailed results into what signaling pathways affect amyloidogenesis in AD induced by obesity. Thus, we investigated the regulatory role of NaB on amyloidogenesis in neuronal cells under high cholesterol. In our results, we verified that increased amyloid β peptide (Aβ) accumulation in the brain of obese mice and a reduction in butyrate-producing bacteria due to the gut microbiota dysbiosis induced by obesity. We showed that NaB decreased the expression levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and Aβ accumulation induced by high cholesterol in SK-N-MC cells. We demonstrated that NaB was absorbed in cells through sodium-coupled monocarboxylate transporter 1 (SMCT1) and then inhibited high cholesterol-induced Aβ accumulation. Subsequently, we also observed that reactive oxygen species (ROS) were overproduced because of increased NADPH oxidase 2 (NOX2) expression under high cholesterol. Meanwhile, NaB decreased NOX2 levels through a reduction of NF-κB activity, which ultimately inhibited Aβ accumulation caused by high cholesterol. We demonstrated that NaB increased the expression levels of p21 under high cholesterol, contributing to p21/NRF2 (Nuclear factor erythroid 2-related factor 2) colocalization, which leads to NRF2 stabilization. NRF2 stabilization causes NF-κB inactivation, followed by NOX2 suppression and superoxide dismutase 1 (SOD1) upregulation. Thus, NaB with SOD1 silencing under high cholesterol did not eliminate excessive ROS, and eventually resulted in Aβ accumulation. In conclusion, we demonstrated that NaB prevents excessive ROS through NOX2 suppression and SOD1 upregulation by p21/NRF2 pathway, which is critical for inhibiting BACE1-dependent amyloidogenesis in neuronal cells exposed to high cholesterol environment.

目前正在研究肠脑轴作为神经系统疾病，特别是阿尔茨海默病（AD）的治疗策略。肥胖会导致肠道微生物群失调，其中包括产生丁酸盐的细菌减少。尽管丁酸钠 (NaB) 已成为 AD 的潜在治疗物质，但对于哪些信号通路影响肥胖引起的 AD 淀粉样蛋白生成，缺乏详细的结果。因此，我们研究了 NaB 对高胆固醇下神经元细胞淀粉样蛋白生成的调节作用。在我们的结果中，我们证实了肥胖小鼠大脑中β淀粉样肽（Aβ）的积累增加，并且由于肥胖引起的肠道微生物群失调，产生丁酸的细菌减少。我们发现 NaB 降低了 SK-N-MC 细胞中高胆固醇诱导的 β 位点淀粉样蛋白前体蛋白裂解酶 1 (BACE1) 的表达水平和 Aβ 积累。我们证明 NaB 通过钠偶联单羧酸转运蛋白 1 (SMCT1) 被细胞吸收，然后抑制高胆固醇诱导的 Aβ 积累。随后，我们还观察到，由于高胆固醇下 NADPH 氧化酶 2 (NOX2) 表达增加，活性氧 (ROS) 产生过量。同时，NaB通过降低NF-κB活性来降低NOX2水平，最终抑制高胆固醇引起的Aβ积累。我们证明，NaB 在高胆固醇条件下增加了 p21 的表达水平，有助于 p21/NRF2（核因子红细胞 2 相关因子 2）共定位，从而导致 NRF2 稳定。NRF2 稳定会导致 NF-κB 失活，进而抑制 NOX2 和上调超氧化物歧化酶 1 (SOD1)。因此，在高胆固醇条件下沉默SOD1的 NaB并不能消除过量的 ROS，最终导致 Aβ 积累。总之，我们证明 NaB 通过抑制 NOX2 和通过 p21/NRF2 途径上调 SOD1 来防止过多的 ROS，这对于抑制暴露于高胆固醇环境的神经元细胞中 BACE1 依赖性淀粉样蛋白形成至关重要。