Drug Development Core, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
Laboratory of Molecular Neuroscience and Dementia, The Brain and Mind Centre, The University of Sydney, Camperdown, NSW, 2050, Australia.
Mol Neurobiol. 2017 Oct;54(8):6074-6084. doi: 10.1007/s12035-016-0125-7. Epub 2016 Oct 3.
Glucagon-like peptide-1 (GLP-1) is an incretin hormone shown to be active in the treatment of type-2 diabetes (T2D) and has also been shown as efficacious in Alzheimer's disease (AD). Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells, rapidly inactivates endogenous GLP-1. Therefore, DPP-4 inhibition is employed as a therapeutic avenue to increase GLP-1 levels in the management of T2D. The effectiveness of DPP-4 inhibitors in the treatment of AD has been reported in various animal models of AD. With this background, the present study was designed to examine the effectiveness of linagliptin, a DPP-4 inhibitor in the 3xTg-AD mouse model of Alzheimer's disease. Nine-month-old 3xTg-AD mice were administered linagliptin orally (5, 10, and 20 mg/kg) for 8 weeks. At the end of the linagliptin treatment, mice were evaluated for cognitive ability on the Morris Water Maze and Y-maze. Following cognitive evaluation, mice were sacrificed to determine the effect of the linagliptin on brain incretin levels, amyloid burden, tau phosphorylation, and neuroinflammation. We confirm that linagliptin treatment for 8 weeks mitigates the cognitive deficits present in 3xTg-AD mice. Moreover, linagliptin also improves brain incretin levels and attenuates amyloid beta, tau phosphorylation as well as neuroinflammation. In conclusion, linagliptin possesses neuroprotective properties that may be attributed to the improvement of incretin levels in the brain.
胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素激素，已被证明在 2 型糖尿病（T2D）的治疗中具有活性，并且在阿尔茨海默病（AD）中也显示出疗效。二肽基肽酶-4（DPP-4）是一种在许多细胞中表达的酶，可迅速使内源性 GLP-1失活。因此，DPP-4 抑制被用作增加 GLP-1 水平以治疗 T2D 的治疗途径。DPP-4 抑制剂在 AD 的各种动物模型中的治疗效果已被报道。在此背景下，本研究旨在研究 DPP-4 抑制剂利拉利汀在阿尔茨海默病 3xTg-AD 小鼠模型中的疗效。9 月龄的 3xTg-AD 小鼠口服给予利拉利汀（5、10 和 20mg/kg）8 周。在利拉利汀治疗结束时，使用 Morris 水迷宫和 Y 迷宫评估小鼠的认知能力。在认知评估后，处死小鼠以确定利拉利汀对大脑肠促胰岛素水平、淀粉样蛋白负担、tau 磷酸化和神经炎症的影响。我们证实利拉利汀治疗 8 周可减轻 3xTg-AD 小鼠的认知缺陷。此外，利拉利汀还可提高大脑肠促胰岛素水平，并减轻淀粉样蛋白β、tau 磷酸化和神经炎症。总之，利拉利汀具有神经保护特性，这可能归因于其改善大脑中的肠促胰岛素水平。
