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

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.