Abstract
IntroductionThere is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Nuclear factor erythroid 2-related factor 2 (Nrf2) is an anti-inflammatory transcription factor that regulates the oxidative stress defense. Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf2 pathway activation. Here, we tested an in vivo kavalactone treatment in a mouse model of AD. MethodsThe kavalactone methysticin was administered once a week for a period of 6 months to 6 month old transgenic APP/Psen1 mice by oral gavage. Nrf2 pathway activation was measured by methysticin treatment of ARE-luciferase mice, by qPCR of Nrf2-target genes and immunohistochemical detection of Nrf2. Aβ burden was analyzed by CongoRed staining, immunofluorescent detection and ELISA. Neuroinflammation was assessed by immunohistochemical stainings for microglia and astrocytes. Pro-inflammatory cytokines in the hippocampus was determined by Luminex multi-plex assays. The hippocampal oxidative damage was detected by oxyblot technique and immunohistochemical staining against DT3 and 4-HNE. The cognitive ability of mice was evaluated using Morris water maze. ResultsMethysticin treatment activated the Nrf2 pathway in the hippocampus and cortex of mice. The Aβ deposition in brains of methysticin-treated APP/Psen1 mice was not altered compared to untreated mice. However, methysticin treatment significantly reduced microgliosis, astrogliosis and secretion of the pro-inflammatory cytokines TNF-α and IL-17A. In addition, the oxidative damage of hippocampi from APP/Psen1 mice was reduced by methysticin treatment. Most importantly, methysticin treatment significantly attenuated the long-term memory decline of APP/Psen1 mice. ConclusionIn summary, these findings show that methysticin administration activates the Nrf2 pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Therefore, kavalactones might be suitable candidates to serve as lead compounds for the development of a new class of neuroprotective drugs.
Highlights
There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD)
We have shown that kavalactones attenuate amyloid ß (Aβ)-peptide toxicity by inducing protective gene expression mediated by the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in vitro [3]
Methysticin treatment resulted in a significant activation of the Nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway in hippocampus (Fig. 1A) and the cortex (Fig. 1B)
Summary
There is increasing evidence for the involvement of chronic inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). Our previous experiments demonstrated that kavalactones protect neuronal cells against Amyloid β (Aβ)-induced oxidative stress in vitro by Nrf pathway activation. Results: Methysticin treatment activated the Nrf pathway in the hippocampus and cortex of mice. The oxidative damage of hippocampi from APP/Psen mice was reduced by methysticin treatment. Conclusion: In summary, these findings show that methysticin administration activates the Nrf pathway and reduces neuroinflammation, hippocampal oxidative damage and memory loss in a mouse model of AD. Alzheimer's disease (AD) is the most common form of dementia and is one of the most expensive diseases for industrial countries It is clinically defined by progressive loss of cognitive and behavioral functions and is histopathologically characterized by amyloid beta deposits, neurofibrillary tangles, synaptic and neuronal loss. Ramsey et al showed that Nrf is localized in the cytosol rather than in the nucleus in both neurons and astrocytes in AD, even if Nrf2-activating oxidative stress and misfolded proteins are present [8]
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