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To determine the availability and the potential molecular mechanisms underlying the therapeutic effect of omaveloxolone (RTA408) on Alzheimer's Disease (AD). This study employed network pharmacology to assess the feasibility of drug treatment of AD. To determine the cognitive status and emotional state of APPswe/PS1dE9 (APP/PS1) mice after the RTA408 treatment, three classical behavioral experiments (water maze, Y-maze, and open field test) were conducted. Immunofluorescence and immunohistochemical staining were utilized to evaluate hippocampal neuronal status and amyloid (Aβ) deposition in mice. RNA-seq and transcription factor prediction analyses were performed to explore the potential molecular mechanisms regulating the therapeutic effects of RTA408. Molecular docking was employed to predict the direct drug targets. To validate these molecular mechanisms, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and immunofluorescence analyses were performed in two instrumental cell lines, i.e., mouse hippocampal neuronal cells (HT22) and microglia (BV2). RTA408 was revealed with the capability to reduce Aβ plaque deposition and to restore damaged neurons in the hippocampal region of APP/PS1 mice, ultimately leading to an improvement in cognitive function. This beneficial effect was achieved by balancing the STAT3 pathway. Specifically, RTA408 facilitated the activations of both STAT3/OXR1 and NRF2/ARE axes, thereby enhancing the compromised resistance in neurons to oxidative stress. RTA408 inhibited the NFκB/IL6/STAT3 pathway, effectively countering the neuroinflammation triggered by microglial activation. RTA408 is revealed with promising potential in the treatment of AD based on preclinical data. [ABSTRACT FROM AUTHOR]

This study aimed to examine the therapeutic effects and response mechanisms of 4-OI in Alzheimer's disease (AD). In this study, network pharmacology was employed to analyze potential targets for AD drug therapy. Immunofluorescence and quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques were utilized to detect inflammatory phenotypes in a 4-OI-resistant mouse microglia cell line (BV2). We conducted four classical behavioral experiments, namely the open field test, new object recognition test, Y maze test, and Morris water maze, to assess the emotional state and cognitive level of APPswe/PS1dE9 (referred to as APP/PS1) mice after 4-OI treatment. Hematoxylin and eosin (HE) staining, along with immunofluorescence staining, were performed to detect amyloid (Aβ) deposition in mouse brain tissue. To explore the potential molecular mechanisms regulating the effects of 4-OI treatment, we performed RNA-SEQ and transcription factor prediction analyses. Additionally, mouse BV2 cells underwent Western blotting analysis to elucidate potential molecular mechanisms underlying the observed effects. We discovered that 4-OI exerts an inhibitory effect on neuroinflammation by promoting autophagy. This effect is attributed to the activation of the AMPK/mTOR/ULK1 pathway, achieved through enhanced phosphorylation of AMPK and ULK1, coupled with a reduction in mTOR phosphorylation. Furthermore, 4-OI significantly enhances neuronal recovery in the hippocampus and diminishes Aβ plaque deposition in APP/PS1 mice, improved anxiety in mice, and ultimately led to improved cognitive function. Overall, the results of this study demonstrated that 4-OI improved cognitive deficits in AD mice, confirming the therapeutic effect of 4-OI on AD. [ABSTRACT FROM AUTHOR]

• Aucubin attenuates Alzheimer's disease-like pathological changes. • Aucubin reduces glial cell activation in the brains of APP/PS1 mice. • Aucubin inhibits LPS-induced activation of BV2 cells and production of inflammatory mediators. • Aucubin attenuates the inflammatory response in Alzheimer's disease via the ERK-FOS axis. Alzheimer's disease (AD) is a degenerative illness accompanied by cognitive and memory loss. In addition to the widely accepted, convincing amyloid cascade hypothesis, the activation of glial cells and neuroinflammation, especially the microglia-mediated neuroinflammation, has an essential role in the development and progression of AD. Therefore, the anti-inflammatory treatment is becoming a promising therapeutic strategy. Aucubin (Au) is a natural product derived from many plants with anti-inflammatory and antioxidant activities. Up to now, no research has been conducted to investigate the anti-inflammatory effects of Au and its neuroprotective quality on AD and the potential molecular mechanisms of its medical roles. In our study, the results of network pharmacology revealed the potential therapeutic effect of Au on AD. The results of studies in vivo showed that Au improved the behaviors, counteracted cognitive and memory deficits, and ameliorated AD-like pathological features of the mouse brain, e.g., the deposition of Aβ plaques, neuronal damage, and inflammatory responses induced by glial cell overactivation, in APP/PS1 mice. The transcriptome sequencing further confirmed that the pathological symptoms of AD could be reversed by inhibiting the ERK/FOS axis to alleviate the inflammatory response. The in vitro experiments revealed that Au suppressed the BV2 cell activation, inhibited the phosphorylation of ERK1/2 and the expression of c-FOS, and reduced the LPS-induced inflammatory mediator production by BV2 cells and primary astrocytes. Our study suggested that Au exerted its neuroprotective effects by inhibiting the inflammatory responses, which could be a promising treatment of AD. [ABSTRACT FROM AUTHOR]