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首页> 外文期刊>Pharmacology, Biochemistry and Behavior >S14G-Humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice
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S14G-Humanin improves cognitive deficits and reduces amyloid pathology in the middle-aged APPswe/PS1dE9 mice

机译：S14G-Humanin改善中年APPswe / PS1dE9小鼠的认知缺陷并减少淀粉样蛋白病理

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摘要

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical cognitive decline and pathological deposition of amyloid-beta protein (Aβ) in the brain. So far, there has been no causative therapy for this devastating disease. S14G-Humanin (HNG), a synthetic derivative of Humanin (HN), has been shown to have strong neuroprotective ability against AD-related insults in vitro and prevent cognitive impairments in Aβ-infused animal models. In addition, a recent study has reported a beneficial effect of intranasal HNG treatment on memory deficit and Aβ accumulation in triple transgenic (3xTg-AD) mice at the early plaque-bearing stage. However, whether HNG treatment has the disease-modifying efficacy on AD with pre-existing well-established amyloid plaque pathology remains unclear. In this study, we employed 9-month-old APPswe/PS1dE9 mice with pre-existing robust amyloid plaque pathology to investigate the effects of chronic HNG treatment on the progression of cognitive dysfunction and Aβ-associated neuropathology. We found that vehicle-treated APPswe/PS1dE9 mice showed impaired spatial learning and memory compared with vehicle- and HNG-treated wild-type mice, while intraperitoneal HNG treatment for 3 months significantly improved spatial learning and memory deficits in APPswe/PS1dE9 mice compared with vehicle control treatment. Coincidental with this, HNG treatment significantly reduced cerebral Aβ plaque deposition, insoluble Aβ levels, and neuroinflammatory responses in APPswe/PS1dE9 mice compared with control treatment. Cumulatively, these findings demonstrate that chronic administration of HNG is able to attenuate cognitive deficits and reduce Aβ loads as well as neuroinflammation in the middle-aged APPswe/PS1dE9 mice even with pre-existing substantial Aβ neuropathology, indicating that HNG has potential as a pharmacotherapeutic intervention in the development of cognitive deficits and neuropathology seen in the cases of established AD.
机译：阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，其特征是临床认知能力下降和脑内淀粉样β蛋白（Aβ）的病理沉积。迄今为止，还没有针对这种破坏性疾病的病因疗法。 S14G-Humanin（HNG）是Humanin（HN）的合成衍生物，已显示出在体外对AD相关损伤具有强大的神经保护能力，并能在注入Aβ的动物模型中预防认知障碍。此外，最近的一项研究报道了鼻内HNG处理对早期携带斑块的三重转基因（3xTg-AD）小鼠记忆缺陷和Aβ积累的有益作用。然而，尚不清楚HNG治疗是否对AD具有预先建立的淀粉样蛋白斑块病理的疾病缓解功效。在这项研究中，我们用9个月大的APPswe / PS1dE9小鼠与预先存在的强力淀粉样蛋白斑病理学研究了慢性HNG治疗对认知功能障碍和Aβ相关神经病理学进展的影响。我们发现，与媒介物和HNG处理的野生型小鼠相比，媒介物处理的APPswe / PS1dE9小鼠显示出空间学习和记忆受损，而与之相比，腹膜内HNG处理3个月显着改善了APPswe / PS1dE9小鼠的空间学习和记忆缺陷车辆控制处理。与此巧合的是，与对照组相比，HNG处理可显着降低APPswe / PS1dE9小鼠的大脑Aβ斑块沉积，不溶性Aβ水平和神经炎症反应。累积地，这些发现表明，即使预先存在实质性Aβ神经病理学，长期服用HNG仍能减轻中年APPswe / PS1dE9小鼠的认知缺陷并减轻Aβ负荷以及神经炎症，这表明HNG具有作为药物治疗的潜力在已建立的AD病例中观察到的对认知缺陷和神经病理学发展的干预。

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