Huangfu Shasha, Sang Xiaoyu, Zhou Shiyue, Liu Haixia, Cui Dongqing, Du Yansheng, Xing Xinyue, Liu Wenyan, Bi Jianzhong, Xie Zhaohong
Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
Department of Neurology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, 264200, China.
Mol Med. 2025 Jun 10;31(1):227. doi: 10.1186/s10020-025-01280-9.
Alzheimer’s disease (AD) is a common neurodegenerative condition characterized by amyloid-β protein (Aβ) deposition, which is central to its pathological changes. Oxidative stress also plays an important role in its pathogenesis. Visinin-like protein 3 (VILIP3), a neuronal calcium sensor protein, is abnormally expressed in the brains of patients with AD; however, the exact mechanism remains unclear. This study investigated the role of abnormal VILIP3 expression in AD pathogenesis and its underlying mechanisms.
We used 5×FAD mice as an in vivo model of AD and Aβ-treated SH-SY5Y cells to construct an in vitro model. Changes in VILIP3 expression were assessed in both models. VILIP3 was overexpressed in the hippocampus of 5×FAD mice and SH-SY5Y cells using adeno-associated virus (AAV) or plasmid transfection. Cognitive function, Aβ deposition, neuronal damage, synaptic plasticity, apoptosis, oxidative stress, and other relevant indices were evaluated.
VILIP3 was expressed at lower levels in AD model mice and cells than in controls. Overexpression of VILIP3 ameliorated cognitive deficits, reduced Aβ deposition and neuronal loss in 5×FAD mice, and attenuated oxidative stress levels and apoptosis in 5×FAD mice and Aβ-treated SH-SY5Y cells. Furthermore, VILIP3 activated nuclear factor E2-related factor 2 (Nrf2) and increased the expression of downstream antioxidant genes. The amelioration of apoptosis and oxidative stress by VILIP3 was blocked by Nrf2-specific inhibitors.
VILIP3 mitigates oxidative stress and apoptosis by activating the Nrf2 signaling pathway, thereby alleviating neuropathological damage and cognitive dysfunction in AD.
The online version contains supplementary material available at 10.1186/s10020-025-01280-9.
阿尔茨海默病（AD）是一种常见的神经退行性疾病，其特征为β淀粉样蛋白（Aβ）沉积，这是其病理变化的核心。氧化应激在其发病机制中也起重要作用。视锥蛋白样蛋白3（VILIP3）是一种神经元钙传感器蛋白，在AD患者大脑中异常表达；然而，确切机制仍不清楚。本研究探讨了VILIP3异常表达在AD发病机制中的作用及其潜在机制。
我们使用5×FAD小鼠作为AD的体内模型，并用Aβ处理SH-SY5Y细胞构建体外模型。在这两种模型中评估VILIP3表达的变化。使用腺相关病毒（AAV）或质粒转染在5×FAD小鼠海马体和SH-SY5Y细胞中过表达VILIP3。评估认知功能、Aβ沉积、神经元损伤、突触可塑性、细胞凋亡、氧化应激及其他相关指标。
与对照组相比，VILIP3在AD模型小鼠和细胞中的表达水平较低。VILIP3过表达改善了5×FAD小鼠的认知缺陷，减少了Aβ沉积和神经元损失，并减轻了5×FAD小鼠以及Aβ处理的SH-SY5Y细胞中的氧化应激水平和细胞凋亡。此外，VILIP3激活了核因子E2相关因子2（Nrf2）并增加了下游抗氧化基因的表达。VILIP3对细胞凋亡和氧化应激的改善作用被Nrf2特异性抑制剂阻断。
VILIP3通过激活Nrf2信号通路减轻氧化应激和细胞凋亡，从而减轻AD中的神经病理损伤和认知功能障碍。
在线版本包含可在10.1186/s10020-025-01280-9获取的补充材料。
