Neuroscience
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Alzheimer's disease (AD) is a progressive neurodegenerative disorder, with no effective method for its treatment so far. The pathogenesis of AD has been reported, but the endogenous metabolic profile and disease-related biomarkers are still not clear. To better understand AD, an AD model induced by injecting β-amyloid 25-35 (Aβ 25-35) solution into bilateral hippocampus was developed on Sprague-Dawley rats. ⋯ The results showed that compared with healthy control rats, AD rats suffered from cognitive dysfunction, hippocampus damage, Aβ formation and tau phosphorylation at 8 weeks after surgery, suggesting that the Aβ25-35-induced AD model was successfully established. In addition, the levels of γ-aminobutyric acid, acetylcholine, glycine, norepinephrine, serotonin, taurine and dopamine decreased and glutamate and aspartic acid increased in hippocampal tissue of AD rats. 45 altered metabolites mainly involved in 8 metabolic pathways were identified as the endogenous biomarkers of AD. According to the analysis of the biological significance of metabolic profiles, the pathogenesis of AD was mainly due to gut microbiome dysbiosis, inhibition of energy metabolism, oxidative stress injury and loss of neuronal protective substances.
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Alzheimer's disease (AD) is the most common cause of dementia in the elderly, characterized by progressive cognitive dysfunction. Aquaporin 9 (AQP9) is an aquaglyceroporin membrane channel shown biophysically to conduct water, glycerol, and other small solutes. In our study, we reported for the first time an age-associated decrease in AQP9 mRNA and protein expressions in both hippocampus and cerebral cortex of APPswe/PS1dE9 (Tg) AD mice at 3, 6 and 10 months of age. ⋯ Pre-treatment with AQP9 small interfering RNA led to a more severe neurotoxicity in PC12 cells in response to Aβ1-40. Furthermore, we corroborated that the active participation of AQP9 in AD progression is associated with Aβ-induced apoptosis both in vitro and in vivo. Taken together, our results reveal an important role of AQP9 in Aβ-induced pathogenesis of AD which deserves further investigation.
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Stimulation of the mu-opioid receptor (MOR) on nociceptors with fentanyl can produce hyperalgesia (opioid-induced hyperalgesia, OIH) and hyperalgesic priming, a model of transition to chronic pain. We investigated if local and systemic administration of biased MOR agonists (PZM21 and TRV130 [oliceridine]), which preferentially activate G-protein over β-arrestin translocation, and have been reported to minimize some opioid side effects, also produces OIH and priming. Injected intradermally (100 ng), both biased agonists induced mechanical hyperalgesia and, when injected at the same site, 5 days later, prostaglandin E2 (PGE2) produced prolonged hyperalgesia (priming). ⋯ Hyperalgesia, analgesia and priming induced by systemic administration of PZM21 were also prevented by MOR AS-ODN. And, priming induced by systemic PZM21 was also not reversed by intradermal cordycepin or the combination of Src and MAPK inhibitors. Thus, maintenance of priming induced by biased MOR agonists, in the peripheral terminal of nociceptors, has a novel mechanism.
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Apolipoprotein E4 (apoE4), one of the three apoE isoforms, is the strongest factor for raising the risk for late-onset Alzheimer's disease (AD) and has been proposed to play a major role in AD pathogenesis. Amyloid-peptide β 42 (Aβ42) has also been proposed to affect neuronal degeneration and AD pathogenesis, possibly by interacting with apoE. Previous studies have shown that the functions of apoE forms can be dictated by their structural and biophysical properties. ⋯ Structural and thermodynamic analyses showed that all three apoE4 mutants have significantly increased α-helical and decreased β-sheet content, have reduced portion of hydrophobic surfaces exposed to the solvent and have a reduced conformational stability during chemical denaturation. Overall, our data highlight a pathogenic role of apoE4 that could be linked to the capacity of the protein to form oligomeric species especially in the presence of Aβ42 and to induce cytotoxicity. Carboxyl-terminal residues L279, K282 or Q284 appear to be involved in the conformation of apoE4 that may underlie the protein's functional properties related to neurotoxicity.
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Audiovisual cuts involve spatial, temporal, and action narrative leaps. They can even change the meaning of the narrative through film editing. Many cuts are not consciously perceived, others are, just as we perceive or not the changes in real events. ⋯ This was reflected by differences in the theta rhythm between 200 and 400 ms, in visual and frontal zones, and can be connected to the different demands that each style of edition makes on working memory and conscious processing after cutting. Also, at the time of cuts, the causality between visual, somatosensory, and frontal networks is altered in any editing style. Our findings suggest that cuts affect media perception and chaotic and fast audiovisuals increase attentional scope but decrease conscious processing.