Dataset Information

Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.

ABSTRACT:

Introduction

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-? (A?) 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, A?, 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. A? 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-1?, IL-6, and TNF-?.

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.

SUBMITTER: Ren P

PROVIDER: S-EPMC7238335 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.

Ren Peng P Chen Jingwei J Li Bingxuan B Zhang Mengzhou M Yang Bei B Guo Xiangshen X Chen Ziyuan Z Cheng Hao H Wang Pengfei P Wang Shuaibo S Wang Ning N Zhang Guohua G Wu Xu X Ma Dan D Guan Dawei D Zhao Rui R

Oxidative medicine and cellular longevity 20200511

<h4>Introduction</h4>Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by the accumulation of amyloid-<i>β</i> (A<i>β</i>) 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 antioxidan ...[more]

PMID: 32454936

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Project description:BackgroundOxidative stress is implicated in the pathogenesis of the most common neurodegenerative diseases, such as Alzheimer's disease (AD). However, tracking oxidative stress in the brain has proven difficult and impeded its use as a biomarker. Herein, we investigate the utility of a novel positron emission tomography (PET) tracer, [18F]ROStrace, as a biomarker of oxidative stress throughout the course of AD in the well-established APP/PS1 double-mutant mouse model. PET imaging studies were conducted in wild-type (WT) and APP/PS1 mice at 3 different time points, representing early (5 mo.), middle (10 mo.), and advanced (16 mo.) life (n = 6-12, per sex). Semi-quantitation SUVRs of the plateau phase (40-60 min post-injection; SUVR40-60) of ten brain subregions were designated by the Mirrione atlas and analyzed by Pmod. Statistical parametric mapping (SPM) was used to distinguish brain regions with elevated ROS in APP/PS1 relative to WT in both sexes. The PET studies were validated by ex vivo autoradiography and immunofluorescence with the parent compound, dihydroethidium.Results[18F]ROStrace retention was increased in the APP/PS1 brain compared to age-matched controls by 10 mo. of age (p < 0.0001) and preceded the accumulation of oxidative damage in APP/PS1 neurons at 16 mo. (p < 0.005). [18F]ROStrace retention and oxidative damages were higher and occurred earlier in female APP/PS1 mice as measured by PET (p < 0.001), autoradiography, and immunohistochemistry (p < 0.05). [18F]ROStrace differences emerged midlife, temporally and spatially correlating with increased Aβ burden (r2 = 0.36; p = 0.0003), which was also greatest in the female brain (p < 0.001).Conclusions[18F]ROStrace identifies increased oxidative stress and neuroinflammation in APP/PS1 female mice, concurrent with increased amyloid burden midlife. Differences in oxidative stress during this crucial time may partially explain the sexual dimorphism in AD. [18F]ROStrace may provide a long-awaited tool to stratify at-risk patients who may benefit from antioxidant therapy prior to irreparable neurodegeneration.

Project description:BackgroundNeuroinflammation is thought to be a cause of Alzheimer's disease (AD), which is partly caused by inadequate mitophagy. As a receptor of mitophagy, we aimed to reveal the regulatory roles of optineurin (OPTN) on neuroinflammation in the pathogenesis of AD.MethodsBV2 cells and APP/PS1 transgenic (Tg) mice were used as in vitro and in vivo experimental models to determine the regulatory roles of OPTN in neuroinflammation of AD. Sophisticated molecular technologies including quantitative (q) RT-PCR, western blot, enzyme linked immunosorbent assay (ELISA), co-immunoprecipitation (Co-IP) and immunofluorescence (IF) were employed to reveal the inherent mechanisms.ResultsAs a consequence, key roles of OPTN in regulating neuroinflammation were identified by depressing the activity of absent in melanoma 2 (AIM2) inflammasomes and receptor interacting serine/threonine kinase 1 (RIPK1)-mediated NF-κB inflammatory mechanisms. In detail, we found that expression of OPTN was downregulated, which resulted in activation of AIM2 inflammasomes due to a deficiency in mitophagy in APP/PS1 Tg mice. By ectopic expression, OPTN blocks the effects of Aβ oligomer (Aβo) on activating AIM2 inflammasomes by inhibiting mRNA expression of AIM2 and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), leading to a reduction in the active form of caspase-1 and interleukin (IL)-1β in microglial cells. Moreover, RIPK1 was also found to be negatively regulated by OPTN via ubiquitin protease hydrolysis, resulting in the synthesis of IL-1β by activating the transcriptional activity of NF-κB in BV2 cells. As an E3 ligase, the UBAN domain of OPTN binds to the death domain (DD) of RIPK1 to facilitate its ubiquitination. Based on these observations, ectopically expressed OPTN in APP/PS1 Tg mice deactivated microglial cells and astrocytes via the AIM2 inflammasome and RIPK-dependent NF-κB pathways, leading to reduce neuroinflammation.ConclusionsThese results suggest that OPTN can alleviate neuroinflammation through AIM2 and RIPK1 pathways, suggesting that OPTN deficiency may be a potential factor leading to the occurrence of AD.

Dataset Information

Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.

Introduction

Methods

Results

Conclusion

Publications

Nrf2 Ablation Promotes Alzheimer's Disease-Like Pathology in APP/PS1 Transgenic Mice: The Role of Neuroinflammation and Oxidative Stress.

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