Nrf2 overexpression ameliorates cognitive deficits and neuronal damage in APP/PS1 mice via attenuation of Aβ deposition and neuronal ferroptosis.

Abstract

Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) deposition, yet the mechanisms underlying Aβ-induced neuronal damage remain elusive. Emerging evidence implicates ferroptosis, an iron-dependent form of regulated cell death, in AD pathology. We hypothesized that dysfunction of the Nrf2 pathway critically links Aβ deposition to neuronal ferroptosis and cognitive decline. In this study, AD progression in APP/PS1 mice was associated with progressive cognitive impairment, Aβ accumulation, and neurodegeneration. Aged APP/PS1 mice exhibited marked suppression of the Nrf2 antioxidant pathway, accumulation of reactive oxygen species, and prominent hallmarks of ferroptosis, including elevated DMT1 and TfR expression, accompanied by reduced GPX4 and xCT expression. Remarkably, genetic overexpression of Nrf2 significantly ameliorated cognitive impairment, attenuated neuronal and synaptic loss, and concurrently reduced Aβ deposition, oxidative stress, and neuronal ferroptosis. These findings demonstrate that Aβ accumulation is associated with impaired Nrf2 signaling during AD progression, leading to oxidative stress, neuronal ferroptosis, and cognitive dysfunction. Collectively, these findings suggest that activation of the Nrf2 pathway exerts robust protective effects against AD-like pathology, highlighting its potential as a therapeutic strategy for AD.