VILIP3 attenuates neuronal apoptosis and oxidative stress via Nrf2 activation in the pathogenesis of Alzheimer's disease

  • Mol Med. 2025 Jun 10;31(1):227. doi: 10.1186/s10020-025-01280-9.
Shasha Huangfu  1 ,  Xiaoyu Sang  1 ,  Shiyue Zhou  1 ,  Haixia Liu  1  2 ,  Dongqing Cui  1 ,  Yansheng Du  1  3 ,  Xinyue Xing  1 ,  Wenyan Liu  1 ,  Jianzhong Bi  1 ,  Zhaohong Xie  4
Affiliations
  • 1. Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
  • 2. Department of Neurology, Weihai Municipal Hospital, Cheeloo College of Medicine, Shandong University, Weihai, 264200, China.
  • 3. Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
  • 4. Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China. [email protected].
PMID: 40495165 DOI: 10.1186/s10020-025-01280-9
Abstract

Background: 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.

Methods: We used 5×FAD mice as an in vivo model of AD and Aβ1−42-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.

Results: 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 Aβ1−42-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.

Conclusions: VILIP3 mitigates oxidative stress and Apoptosis by activating the Nrf2 signaling pathway, thereby alleviating neuropathological damage and cognitive dysfunction in AD.

Supplementary Information: The online version contains supplementary material available at 10.1186/s10020-025-01280-9.

Keywords
Alzheimer’s disease; Apoptosis; Neuroprotection; Nrf2; Oxidative stress; VILIP3.
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