Nrf2 Ablation Promotes Alzheimer’s Disease-Like Pathology in APPPS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress

Abstract EN

Introduction.

Alzheimer’s disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-β (Aβ) peptide and hyperphosphorylated tau protein.

Accumulating evidence has revealed that the slow progressive deterioration of AD is associated with oxidative stress and chronic inflammation in the brain.

Nuclear factor erythroid 2- (NF-E2-) related factor 2 (Nrf2), which acts through the Nrf2/ARE pathway, is a key regulator of the antioxidant and anti-inflammatory response.

Although recent data show a link between Nrf2 and AD-related cognitive decline, the mechanism is still unknown.

Thus, we explored how Nrf2 protects brain cells against the oxidative stress and inflammation of AD in a mouse model of AD (APP/PS1 transgenic (AT) mice) with genetic removal of Nrf2.

Methods.

The spatial learning and memory abilities of 12-month-old transgenic mice were evaluated using a Morris water maze test.

Hippocampal levels of Nrf2, Aβ, and p-tauS404 and of astrocytes and microglia were determined by immunostaining.

Inflammatory cytokines were determined by ELISA and quantitative real-time polymerase chain reaction (qRT-PCR).

Oxidative stress was measured by 8-hydroxydeoxyguanosine immunohistochemistry, and the antioxidant response was determined by qRT-PCR.

Results.

The spatial learning and memory abilities of AT mice were impaired after Nrf2 deletion.

Aβ and p-tauS404 accumulation was increased in the hippocampus of AT/Nrf2-KO mice.

Astroglial and microglial activation was exacerbated, followed by upregulation of the proinflammatory cytokines IL-1β, IL-6, and TNF-α.

Conclusion.

Our present results show that Nrf2 deficiency aggravates AD-like pathology in AT mice.

This phenotype was associated with increased levels of oxidative and proinflammatory markers, which suggests that the Nrf2 pathway may be a promising therapeutic target for AD.