Quercetin Attenuates Oxidative Stress and Apoptosis in Brain Tissue of APP/PS1 Double Transgenic AD Mice by Regulating Keap1/Nrf2/HO-1 Pathway to Improve Cognitive Impairment.

Objective: The objective of the study is to investigate whether quercetin ameliorates Alzheimer's disease (AD)-like pathology in APP/PS1 double transgenic mice and its hypothesized mechanism, contributing to the comprehension of AD pathogenesis. Methods: A total of 30 APP/PS1 transgenic mice were randomized into model group (APP/PS1), quercetin group (APP/PS1+Q), and donepezil hydrochloride group (APP/PS1+DON). Simultaneously, there were 10 C57 mice of the same age served as a control group. Three months posttreatment, the effects of quercetin on AD mice were evaluated using the Morris water maze (MWM) test, Y maze experiment, immunohistochemistry, immunofluorescence, and western blotting. Results: Results from the water maze and Y maze indicated that quercetin significantly improved cognitive impairment in APP/PS1 transgenic AD mice. Additionally, serum enzyme-linked immunosorbent assay (ELISA) results demonstrated that quercetin elevated MDA, superoxide dismutase (SOD), CAT, GSH, acetylcholine (ACh), and acetylcholinesterase (AChE) levels in AD mice. Hematoxylin-eosin (HE) staining, Nissl staining, and hippocampal tissue thioflavine staining revealed that quercetin reduced neuronal damage and Aβ protein accumulation in AD mice. Western blot validated protein expression in the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathway associated with oxidative stress and apoptosis, confirming quercetin's potential molecular mechanism of enhancing AD mouse cognition. Furthermore, western blot findings indicate that quercetin significantly alters protein expression in the Keap1/Nrf2/HO-1 pathway. Moreover, molecular docking analysis suggests that Keap1, NQO1, HO-1, caspase-3, Bcl-2, and Bax proteins in the Keap1/Nrf2/HO-1 pathway may be potential regulatory targets of quercetin. These findings will provide a molecular basis for quercetin's clinical application in AD treatment. Conclusion: Quercetin can improve cognitive impairment and AD-like pathology in APP/PS1 double transgenic mice, potentially related to quercetin's activation of the Keap1/Nrf2/HO-1 pathway and reduction of cell apoptosis.

Cheng M ，Yuan C ，Ju Y ，Liu Y ，Shi B ，Yang Y ，Jin S ，He X ，Zhang L ，Min D ... -  《-》

DJ1 Ameliorates AD-like Pathology in the Hippocampus of APP/PS1 Mice.

Peng YY ，Li MX ，Li WJ ，Xue Y ，Miao YF ，Wang YL ，Fan XC ，Tang LL ，Song HL ，Zhang Q ，Li X ... -  《-》

Qifu-yin activates the Keap1/Nrf2/ARE signaling and ameliorates synaptic injury and oxidative stress in APP/PS1 mice.

The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated. This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement. The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aβ) aggregation was detected via immunostaining, while the quantification of Aβ1-40 and Aβ1-42 was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aβ metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot. A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY. QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.

Wang S ，Huang J ，Chen Y ，Liang Y ，Chen L ，Ye D ，Yang H ，Hui Z ，Wang X ，Zhang Z ，Zhu X ... -  《-》

Lithium chloride reduced the level of oxidative stress in brains and serums of APP/PS1 double transgenic mice via the regulation of GSK3β/Nrf2/HO-1 pathway.

Xiang J ，Cao K ，Dong YT ，Xu Y ，Li Y ，Song H ，Zeng XX ，Ran LY ，Hong W ，Guan ZZ ... -  《-》

Astragalus polysaccharide alleviates cognitive impairment and β-amyloid accumulation in APP/PS1 mice via Nrf2 pathway.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and its etiology and pathogenesis are not fully understood. Astragalus polysaccharide (APS) has many pharmacological activities, but there are few reports about its role in AD. Using the common AD model APP/PS1 mice, it was found that the expression of Keap1 (a negative regulatory factor of Nrf2), the protein level of cytoplasmic Nrf2 and the content of MDA were increased significantly, while the mRNA level of Nrf2, the expression of Nrf2 in nucleus and the contents of SOD and GSH-Px were decreased significantly. APS treatment significantly increased the expression of Nrf2 in the nucleus but decreased its expression in the cytoplasm, and restored the expression levels of Keap1, SOD, GSH-Px and MDA. When APP/PS1 mice were treated with APS and injected with Nrf2 siRNA, the down-regulation of Nrf2 expression significantly blocked the regulation of APS on oxidative stress. Continuing to test the physiological function of AD mice showed that the spatial learning and memory abilities of APP/PS1 mice were impaired, the apoptosis of brain cells and the content of β-amyloid (Aβ) were significantly increased. APS treatment significantly improved the cognitive ability of APP/PS1 mice, reduced apoptosis and the accumulation of Aβ, but the above effects of APS were blocked by Nrf2 siRNA injection. Therefore, APS can activate Nrf2 pathway to improve the physiological function of AD mice, which may have important clinical application value.

Qin X ，Hua J ，Lin SJ ，Zheng HT ，Wang JJ ，Li W ，Ke JJ ，Cai HB ... -  《-》