Neuroscience
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Tau protein hyperphosphorylation and formation of intracellular neurofibrillary tangles (NFTs) are one of the histopathological hallmarks of Alzheimer's disease (AD) and positively correlated with the severity of AD symptoms. NFTs contain a large number of metal ions that play an important role in regulating tau protein phosphorylation and AD progression. Extracellular tau induces primary phagocytosis of stressed neurons and neuronal loss by activating microglia. ⋯ Treatment with DpdtpA also suppressed tau protein expression and phosphorylation. Moreover, treatment with DpdtpA prevented tau-induced activation of glycogen synthase kinase-3β (GSK-3β) and inhibition of phosphatidylinositol-3-hydroxy kinase (PI3K)/AKT. Collectively, these results show that DpdtpA can attenuate tau phosphorylation and inflammatory responses of microglia by regulating the PI3K/AKT/GSK-3β signal pathways, providing a new option to alleviate neuroinflammation for the treatment of AD.
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Environmental enrichment (EE) is a condition characterized by its complexity regarding social contact, exposure to novelty, tactile stimuli and voluntary exercise, also is considered as a eustress model. The impact of EE on brain physiology and behavioral outcomes may be at least partly underpinned by mechanisms involving the modulation of the brain-derived neurotrophic factor (BDNF), but the connection between specific Bdnf exon expression and their epigenetic regulation remain poorly understood. This study aimed to dissect the transcriptional and epigenetic regulatory effect of 54-day exposure to EE on BDNF by analysing individual BDNF exons mRNA expression and the DNA methylation profile of a key transcriptional regulator of the Bdnf gene, exon IV, in the prefrontal cortex (PFC) of C57BL/6 male mice (sample size = 33). ⋯ However, no changes were observed in EE mice. The findings may suggest an EE-induced epigenetic control of BDNF exon expression via a mechanism involving exon IV methylation. The findings of this study contribute to the current literature by dissecting the Bdnf gene topology in the PFC where transcriptional and epigenetic regulatory effect of EE takes place.
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Visually guided reaching is a common motor behavior that engages subcortical circuits to mediate rapid corrections. Although these neural mechanisms have evolved for interacting with the physical world, they are often studied in the context of reaching toward virtual targets on a screen. These targets often change position by disappearing from one place reappearing in another instantaneously. ⋯ In one condition, the objects moved very rapidly from one place to another. In the other condition, illuminated targets instantaneously switched position by being extinguished in one position and illuminating in another. Participants were consistently faster in correcting their reach trajectories when the object moved continuously.
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Ischemic stroke is one of the main causes of serious disability and death worldwide. NLRP3 inflammasome is an intracellular pattern recognition receptor composed of polyprotein complex, which participates in mediating a series of inflammatory responses and is considered as a potential target for the treatment of ischemic stroke. Vinpocetine, a derivative of vincamine, has been widely used in the prevention and treatment of ischemic stroke. ⋯ Vinpocetine can effectively inhibit the apoptosis of peri-infarct neurons, promote the expression of Bcl-2, inhibit the expression of Bax and Cleaved Caspase-3, and reduce the proliferation of peri-infarct microglia. In addition, vinpocetine, like MCC950, can reduce the expression of NLRP3 inflammasome. Therefore, vinpocetine can effectively alleviate the ischemia-reperfusion injury in mice, and the inhibition of NLRP3 inflammasome may be an important therapeutic mechanism of vinpocetine.
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The major immune cells of the central nervous systems (CNS) are microglia and astrocytes, subsets of the glial cell population. The crosstalk between glia via soluble signaling molecules plays an indispensable role for neuropathologies, brain development as well as homeostasis. However, the investigation of the microglia-astrocyte crosstalk has been hampered due to the lack of suitable glial isolation methods. ⋯ Finally, co-culturing microglia and astrocytes confirmed the prior results by demonstrating a significant TNF release by WT microglia co-cultured with TLR2-KO astrocytes. Our findings suggest a molecular TLR2/1-dependent conversation between highly pure activated microglia and astrocytes via signaling molecules. Furthermore, we demonstrate the first crosstalk experiments using ∼100% pure microglia and astrocyte mono-/co-cultures derived from mice with different genotypes highlighting the urgent need of efficient glial isolation protocols, which particularly holds true for astrocytes.