Obesity and Metabolic Health Laboratory, Department of Nutritional Sciences, Texas Tech University, Lubbock, TX 79409, USA.
Internal Medicine, Cell Biology and Biochemistry, Neuroscience/Pharmacology and Neurology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
Biochim Biophys Acta Mol Basis Dis. 2019 Nov 1;1865(11):165531. doi: 10.1016/j.bbadis.2019.08.007. Epub 2019 Aug 6.
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide. While the causes of AD are unclear, several risk factors have been identified, including impaired glycemic control, which significantly increases the risk of cognitive decline and AD. In vitro and in vivo studies show that human adenovirus 36 (Ad36) improves glycemic control by increasing cellular glucose uptake in cells, experimental animal models and in humans who are naturally exposed to the virus. This study, tested improvement in glycemic control by Ad36 and delay in onset of cognitive decline in APPswe transgenic mice (Tg2576 line), a model of genetic predisposition to impaired glycemic control and AD. Three-month old APPswe mice were divided into Ad36 infected (Ad36) or mock infected (control) groups and baseline glycemic control measured by glucose tolerance test (GTT) prior to infection. Changes in glycemic control were determined 10- and 24-week post infection. Serum insulin was also measured during GTT. Cognition was determined by Y-maze test, while motor coordination and skill acquisition by rotarod test. Glycemic control as determined by GTT showed less deterioration in Ad36 infected mice over time, accompanied by a significant attenuation of cognitive decline. Analysis of brain tissue lysate showed significantly reduced levels of amyloid beta 42 in Ad36 mice relative to control mice. Golgi-Cox staining analysis also revealed reduced dendritic spines and synaptic gene expression in control mice compared to Ad36 infected mice. This proof of concept study shows that in a mouse model of AD, Ad36 improves glycemic control and ameliorates cognitive decline.
阿尔茨海默病（AD）是全球最常见的神经退行性疾病。虽然 AD 的病因尚不清楚，但已经确定了一些危险因素，包括血糖控制受损，这会显著增加认知能力下降和 AD 的风险。体外和体内研究表明，人腺病毒 36（Ad36）通过增加细胞对葡萄糖的摄取，来改善血糖控制，这种作用在实验动物模型和自然感染该病毒的人群中得到了验证。本研究旨在测试 Ad36 是否可以改善血糖控制，并延缓 APPswe 转基因小鼠（Tg2576 系）的认知能力下降的发病，该模型存在血糖控制受损和 AD 的遗传易感性。将 3 个月大的 APPswe 小鼠分为 Ad36 感染（Ad36）或模拟感染（对照）组，并在感染前通过葡萄糖耐量试验（GTT）测量基线血糖控制情况。感染后 10 周和 24 周分别测定血糖控制的变化。在 GTT 期间还测量了血清胰岛素。通过 Y 迷宫试验测定认知，通过转棒试验测定运动协调和技能获得。GTT 测定的血糖控制显示，随时间推移，Ad36 感染的小鼠血糖控制恶化程度较低，同时认知能力下降也明显减弱。脑组织裂解物分析显示，Ad36 组小鼠的淀粉样蛋白β 42 水平明显低于对照组。高尔基-考克斯染色分析还显示，与 Ad36 感染的小鼠相比，对照组小鼠的树突棘和突触基因表达减少。本概念验证研究表明，在 AD 的小鼠模型中，Ad36 可改善血糖控制并改善认知能力下降。
