The burden of Alzheimer’s disease, the most prevalent neurodegenerative disease, is increasing exponentially due to the increase in the elderly population worldwide. Synaptic plasticity is the basis of learning and memory, but it is impaired in AD. Uncovering the disease’s underlying molecular pathogenic mechanisms involving synaptic plasticity could lead to the identification of targets for better disease management. Using primary neurons treated with Aβ and APP/PS1 animal models, we evaluated the effect of the phenolic compound ferulic acid (FA) on synaptic dysregulations. Aβ led to synaptic plasticity and cognitive impairments by increasing STEP activity and decreasing the phosphorylation of the GluN2B subunit of NMDA receptors, as well as decreasing other synaptic proteins, including PSD-95 and synapsin1. Interestingly, FA attenuated the Aβ-upregulated intracellular calcium and thus resulted in a decrease in PP2B-induced activation of DARPP-32, inhibiting PP1. This cascade event maintained STEP in its inactive state, thereby preventing the loss of GluN2B phosphorylation. This was accompanied by an increase in PSD-95 and synapsin1, improved LTP, and a decreased Aβ load, together leading to improved behavioral and cognitive functions in APP/PS1 mice treated with FA. This study provides insight into the potential use of FA as a therapeutic strategy in AD.

阿尔茨海默病是最常见的神经退行性疾病，由于全球老年人口的增加，其负担呈指数级增加。突触可塑性是学习和记忆的基础，但在 AD 中却受到损害。揭示该疾病涉及突触可塑性的潜在分子致病机制可能有助于确定更好的疾病管理目标。使用经 Aβ 和 APP/PS1 动物模型处理的原代神经元，我们评估了酚类化合物阿魏酸 (FA) 对突触失调的影响。 Aβ 通过增加 STEP 活性、减少 NMDA 受体 GluN2B 亚基的磷酸化以及减少其他突触蛋白（包括 PSD-95 和 synapsin1）而导致突触可塑性和认知障碍。有趣的是，FA 减弱了 Aβ 上调的细胞内钙，从而导致 PP2B 诱导的 DARPP-32 激活减少，从而抑制 PP1。该级联事件使 STEP 保持在非活性状态，从而防止 GluN2B 磷酸化的丧失。伴随着 PSD-95 和突触蛋白 1 的增加、LTP 的改善和 Aβ 负荷的减少，共同导致接受 FA 治疗的 APP/PS1 小鼠的行为和认知功能得到改善。这项研究深入探讨了 FA 作为 AD 治疗策略的潜在用途。