School of Biomedical Sciences, Ulster University, Coleraine, UK.
Neurobiol Aging. 2012 Feb;33(2):265-76. doi: 10.1016/j.neurobiolaging.2010.02.014. Epub 2010 Mar 31.
Diabetes is a risk factor for Alzheimer's disease. We tested the effects of Val(8)GLP-1, an enzyme-resistant analogue of the incretin hormone glucagon-like peptide 1 originally developed to treat diabetes in a mouse model of Alzheimer's disease that expresses mutated amyloid precursor protein (APP) and presenilin-1. We tested long term potentiation (LTP) of synaptic plasticity, inflammation response, and plaque formation. Val(8)GLP-1 crosses the blood-brain barrier when administered via intraperitoneal injection. Val(8)GLP-1 protected LTP in 9- and 18-month-old Alzheimer's disease mice when given for 3 weeks at 25 nmol/kg intraperitoneally. LTP was also enhanced in 18-month-old wild type mice, indicating that Val(8)GLP-1 also ameliorates age-related synaptic degenerative processes. Paired-pulse facilitation was also enhanced. The number of beta-amyloid plaques and microglia activation in the cortex increased with age but was not reduced by Val(8)GLP-1. In 18-month-old mice, however, the number of Congo red positive dense-core amyloid plaques was reduced. Treatment with Val(8)GLP-1 might prevent or delay neurodegenerative processes.
糖尿病是阿尔茨海默病的一个风险因素。我们在一种阿尔茨海默病的小鼠模型中测试了 Val(8)GLP-1 的作用，该模型表达突变的淀粉样前体蛋白 (APP) 和早老素-1。Val(8)GLP-1 是胰高血糖素样肽 1 的一种酶抗性类似物，最初是为治疗糖尿病而开发的。我们测试了突触可塑性、炎症反应和斑块形成的长时程增强 (LTP)。当通过腹腔内注射给予时，Val(8)GLP-1 可以穿过血脑屏障。Val(8)GLP-1 在给予 25nmol/kg 腹腔内 3 周时可保护 9 个月和 18 个月大的阿尔茨海默病小鼠的 LTP。18 个月大的野生型小鼠的 LTP 也增强了，表明 Val(8)GLP-1 还改善了与年龄相关的突触退行性过程。也增强了成对脉冲易化。皮质中β-淀粉样斑块和小胶质细胞激活的数量随年龄增加而增加，但 Val(8)GLP-1 并未减少。然而，在 18 个月大的小鼠中，刚果红阳性致密核心淀粉样斑块的数量减少了。Val(8)GLP-1 的治疗可能预防或延迟神经退行性过程。
