Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Neurobiol Aging. 2019 Mar;75:98-108. doi: 10.1016/j.neurobiolaging.2018.11.008. Epub 2018 Nov 17.
Type 2 diabetes mellitus (T2DM) increases the risk for Alzheimer's disease (AD). Human AD brains show reduced glucose metabolism as measured by [18F]fluoro-2-deoxy-2-D-glucose positron emission tomography (FDG-PET). Here, we used 14-month-old wild-type (WT) and APP/PS1 (APP/PS1) transgenic mice to investigate how a single dose of intranasal insulin modulates brain glucose metabolism using FDG-PET and affects spatial learning and memory. We also assessed how insulin influences the activity of Akt1 and Akt2 kinases, the expression of glial and neuronal markers, and autophagy in the hippocampus. Intranasal insulin moderately increased glucose metabolism and specifically activated Akt2 and its downstream signaling in the hippocampus of WT, but not APP/PS1 mice. Furthermore, insulin differentially affected the expression of homeostatic microglia markers P2ry12 and Cx3cr1 and autophagy in the hippocampus of WT and APP/PS1 mice. We found no evidence that a single dose of intranasal insulin improves overnight memory. Our results suggest that intranasal insulin exerts diverse effects on Akt2 signaling, autophagy, and the homeostatic status of microglia depending on the degree of AD-related pathology.
2 型糖尿病（T2DM）增加了阿尔茨海默病（AD）的风险。人类 AD 大脑表现出葡萄糖代谢减少，这可以通过 [18F]氟代-2-脱氧-2-D-葡萄糖正电子发射断层扫描（FDG-PET）测量。在这里，我们使用 14 个月大的野生型（WT）和 APP/PS1（APP/PS1）转基因小鼠来研究单次鼻内胰岛素给药如何使用 FDG-PET 调节大脑葡萄糖代谢，并影响空间学习和记忆。我们还评估了胰岛素如何影响 Akt1 和 Akt2 激酶的活性、神经胶质和神经元标志物的表达以及海马体中的自噬。鼻内胰岛素适度增加了 WT 但不是 APP/PS1 小鼠大脑中的葡萄糖代谢，并特异性激活了海马体中的 Akt2 及其下游信号。此外，胰岛素对 WT 和 APP/PS1 小鼠海马体中稳态小胶质细胞标志物 P2ry12 和 Cx3cr1 的表达和自噬有不同的影响。我们没有发现证据表明单次鼻内胰岛素给药可以改善夜间记忆。我们的结果表明，鼻内胰岛素根据 AD 相关病理的程度对 Akt2 信号、自噬和小胶质细胞的稳态状态产生不同的影响。
