Department of Neurology, Tangdu Hospital, Fourth Military Medical University, Xi'an City, Shaanxi Province 710038, China.
Pharmacol Biochem Behav. 2012 Jan;100(3):361-9. doi: 10.1016/j.pbb.2011.09.012. Epub 2011 Oct 2.
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.
阿尔茨海默病（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）病理性沉积。迄今为止，针对这种破坏性疾病还没有病因治疗方法。S14G-人源神经保护肽（HNG）是人源神经保护肽（HN）的合成衍生物，已被证明在体外具有很强的抗 AD 相关损伤的神经保护能力，并可预防 Aβ 注入动物模型中的认知障碍。此外，最近的一项研究报道了鼻内 HNG 治疗对早期有斑块的三转基因（3xTg-AD）小鼠记忆缺陷和 Aβ 积累的有益作用。然而，HNG 治疗是否对已经存在成熟淀粉样斑块病理的 AD 具有疾病修饰作用尚不清楚。在这项研究中，我们使用了 9 月龄的 APPswe/PS1dE9 小鼠，其已经存在强大的淀粉样斑块病理，以研究慢性 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 vehicle-和 HNG-处理的野生型小鼠相比，vehicle 处理的 APPswe/PS1dE9 小鼠表现出空间学习和记忆受损，而 HNG 腹腔内治疗 3 个月可显著改善 APPswe/PS1dE9 小鼠的空间学习和记忆障碍与对照治疗相比。与此一致的是，HNG 治疗可显著降低 APPswe/PS1dE9 小鼠大脑中的 Aβ 斑块沉积、不溶性 Aβ 水平和神经炎症反应，与对照治疗相比。总之，这些发现表明，慢性给予 HNG 能够减轻认知障碍，并降低中年 APPswe/PS1dE9 小鼠的 Aβ 负荷和神经炎症，即使存在大量的 Aβ 神经病理学，这表明 HNG 具有作为治疗 AD 认知障碍和神经病理学的药物干预的潜力。
