Department of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.
J Alzheimers Dis. 2013;37(3):637-48. doi: 10.3233/JAD-130491.
BACKGROUND/OBJECTIVE: Type 2 diabetes increases the risk for developing Alzheimer's disease (AD), a progressive neurodegenerative disorder. Brain insulin resistance contributes to the pathogenesis of AD, and abnormal hyperphosphorylation of tau protein is crucial to neurodegeneration. Here we studied whether liraglutide, an agonist of glucagon-like peptide-1 (GLP-1) and a new anti-diabetic drug, can promote brain insulin signaling and inhibit tau hyperphosphorylation in the brains of type 2 diabetic rats.
Type 2 diabetic rats were treated with subcutaneous administration of liraglutide (0.2 mg/kg body weight) or, as a control, saline twice a day for up to four weeks. Blood, cerebrospinal fluid (CSF), and brain tissue (n = 7 each group) were collected for analyses after liraglutide or saline administration for one, two, three, and four weeks.
We found decreased CSF insulin, hyperphosphorylation of tau at AD-relevant phosphorylation sites, and decreased phosphorylation of protein kinase B (AKT) and glycogen synthase kinase-3β (GSK-3β) in the brain, which indicated decreased insulin signaling leading to overactivation of GSK-3β, a major tau kinase, in type 2 diabetic rats. Liraglutide treatment not only ameliorated hyperglycemia and peripheral insulin resistance, but also reversed these brain abnormalities in a time-dependent manner.
Our results indicated that subcutaneous administration of liraglutide restores both peripheral and brain insulin sensitivity and ameliorates tau hyperphosphorylation in rats with type 2 diabetes. These findings support the potential use of liraglutide for the prevention and treatment of AD in individuals with type 2 diabetes.
背景/目的：2 型糖尿病会增加阿尔茨海默病（AD）的发病风险，AD 是一种进行性神经退行性疾病。脑胰岛素抵抗导致 AD 的发病机制，tau 蛋白的异常过度磷酸化对神经退行性变至关重要。在这里，我们研究了胰高血糖素样肽-1（GLP-1）激动剂利拉鲁肽（一种新型抗糖尿病药物）是否可以促进 2 型糖尿病大鼠的脑胰岛素信号转导并抑制 tau 过度磷酸化。
2 型糖尿病大鼠每天两次皮下注射利拉鲁肽（0.2 mg/kg 体重）或生理盐水（作为对照），持续 4 周。在利拉鲁肽或生理盐水给药 1、2、3 和 4 周后，每组采集 7 只大鼠的血液、脑脊液（CSF）和脑组织进行分析。
我们发现 CSF 胰岛素减少，AD 相关磷酸化位点的 tau 过度磷酸化，以及大脑中蛋白激酶 B（AKT）和糖原合酶激酶-3β（GSK-3β）的磷酸化减少，这表明胰岛素信号转导减少导致 GSK-3β过度激活，GSK-3β 是 tau 激酶的主要激酶。利拉鲁肽治疗不仅改善了高血糖和外周胰岛素抵抗，而且还以时间依赖性方式逆转了这些脑部异常。
我们的结果表明，皮下注射利拉鲁肽不仅恢复了外周和脑胰岛素敏感性，而且改善了 2 型糖尿病大鼠的 tau 过度磷酸化。这些发现支持利拉鲁肽用于预防和治疗 2 型糖尿病患者 AD 的潜在用途。
