Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.
Oxid Med Cell Longev
; 2020: 3050971, 2020.
Article
de En
| MEDLINE
| ID: mdl-32454936
ABSTRACT
INTRODUCTION:
Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-ß (Aß) 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, Aß, 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. Aß 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-1ß, 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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Encéphale
/
Peptides bêta-amyloïdes
/
Stress oxydatif
/
Facteur-2 apparenté à NF-E2
/
Préséniline-1
/
Maladie d'Alzheimer
/
Inflammation
Type d'étude:
Prognostic_studies
Limites:
Animals
Langue:
En
Journal:
Oxid Med Cell Longev
Sujet du journal:
METABOLISMO
Année:
2020
Type de document:
Article
Pays d'affiliation:
Chine