Nasal Delivery of D-Penicillamine Hydrogel Upregulates a Disintegrin and Metalloprotease 10 Expression via Melatonin Receptor 1 in Alzheimer's Disease Models.
Nasal Delivery of D-Penicillamine Hydrogel Upregulates a Disintegrin and Metalloprotease 10 Expression via Melatonin Receptor 1 in Alzheimer's Disease Models.
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在阿尔茨海默病模型中，D-青霉胺水凝胶经鼻给药通过褪黑素受体 1 上调解整合素和金属蛋白酶 10 的表达
DOI：
10.3389/fnagi.2021.660249
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发表时间：
2021
影响因子：
4.8
通讯作者：
Gao H
中科院分区：
文献类型：
--
作者：
Zhong M;Kou H;Zhao P;Zheng W;Xu H;Zhang X;Lan W;Guo C;Wang T;Guo F;Wang Z;Gao H
阿尔茨海默病（AD）是一种与淀粉样斑块积累相关的神经退行性疾病。增加非淀粉样蛋白加工和/或操纵淀粉样蛋白前体蛋白信号传导可以减少AD淀粉样蛋白病理和认知障碍。D-青霉胺（D-Pen）是一种水溶性金属螯合剂，在体外可减少Aβ与金属的聚集。然而，D-Pen用于治疗神经退行性疾病的潜在机制仍未探索。本文设计了一种新型的壳聚糖基水凝胶载体D-Pen，并通过扫描电镜和高效液相色谱对D-Pen-CS/β-甘油磷酸水凝胶进行了表征。行为测试研究了通过D-Pen水凝胶鼻递送治疗的APP/PS1小鼠的学习和记忆水平。体内和体外研究结果表明，D-Pen-CS/β-GP水凝胶鼻腔给药具有适当的螯合金属离子，减少了Aβ沉积。此外，D-Pen主要通过褪黑素受体1 α（MTNR 1 α）和下游PKA/ERK/CREB通路调节A去整合素和金属蛋白酶10（ADAM 10）的表达。目前的数据表明，D-Pen通过激活ADAM 10和加速非淀粉样蛋白生成加工，显著改善APP/PS1小鼠的认知能力，减少Aβ生成。因此，这些发现表明D-Pen作为治疗AD的有希望的药剂的潜力。
Alzheimer’s disease (AD) is a type of neurodegenerative disease that is associated with the accumulation of amyloid plaques. Increasing non-amyloidogenic processing and/or manipulating amyloid precursor protein signaling could reduce AD amyloid pathology and cognitive impairment. D-penicillamine (D-Pen) is a water-soluble metal chelator and can reduce the aggregation of amyloid-β (Aβ) with metals in vitro. However, the potential mechanism of D-Pen for treating neurodegenerative disorders remains unexplored. In here, a novel type of chitosan-based hydrogel to carry D-Pen was designed and the D-Pen-CS/β-glycerophosphate hydrogel were characterized by scanning electron microscopy and HPLC. Behavior tests investigated the learning and memory levels of APP/PS1 mice treated through the D-Pen hydrogel nasal delivery. In vivo and in vitro findings showed that nasal delivery of D-Pen-CS/β-GP hydrogel had properly chelated metal ions that reduced Aβ deposition. Furthermore, D-Pen mainly regulated A disintegrin and metalloprotease 10 (ADAM10) expression via melatonin receptor 1 (MTNR1α) and the downstream PKA/ERK/CREB pathway. The present data demonstrated D-Pen significantly improved the cognitive ability of APP/PS1 mice and reduced Aβ generation through activating ADAM10 and accelerating non-amyloidogenic processing. Hence, these findings indicate the potential of D-Pen as a promising agent for treating AD.
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影响因子：
5.4
作者：
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通讯作者：
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