Neuroscience
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Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of elderly dementia in the world. At present, acetylcholine inhibitors, such as donepezil, galantamine and rivastigmine, are used for AD therapy, but the therapeutic efficacy is limited. We recently proposed T-type voltage-gated Ca2+ channels' (T-VGCCs) enhancer as a new therapeutic candidate for AD. ⋯ Chronic SAK3 (0.5 mg/kg/day) oral administration for 3 months from 9 months of age improved cognitive function and inhibited Aβ deposition in 12-month-old NL-F mice. Using microarray and real-time PCR analysis, we discovered serum- and glucocorticoid-induced protein kinase 1 (SGK1) as one of possible genes involved in the inhibition of Aβ deposition and improvement of cognitive function by SAK3. These results support the idea that T-VGCC enhancer, SAK3 could be a novel candidate for disease-modifying therapeutics for AD.
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Post-stroke hyperglycemia during early reperfusion increases blood-brain barrier (BBB) permeability and subsequently aggravates brain injury and clinical prognosis. The decreased level of tight junction proteins (TJPs) has been reported but the underlying mechanism remains largely elusive. Herein we designed to investigate the detailed molecular events in brain microvascular endothelial cells (BMECs) ex and in vivo. ⋯ Therefore, high-glucose exposure in the early reperfusion causes the BBB disruption, with MMP-2/9-mediated extracellular degradation, caveolin-1-mediated intracellular translocation and autophagy-lysosome-mediated degradation of ZO-1 protein all together involved in the process. The role of MMP-2/-9 and autophagy in the modulation of paracellular permeability was confirmed by pharmacological inhibition. Therefore, our findings may provide new insights into targeting ZO-1 regulation for the purpose of significantly improving the clinical prognosis of ischemic stroke.