Wang Lushan, Curran Geoffry L, Zhong Rui, Xue Zheng, Veerareddy Vaishnavi, Thieschafer Josslen, Min Paul H, Li Ling, Lowe Val J, Kandimalla Karunya K
Department of Pharmaceutics and Brain Barriers Research Center, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Radiology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
J Cereb Blood Flow Metab. 2025 May 15:271678X251332493. doi: 10.1177/0271678X251332493.
Molecular mechanisms underlying disruptions in brain glucose uptake and metabolism, linked with cognitive decline in Alzheimer's disease (AD) patients, are only partially understood. This study investigated how soluble amyloid beta (sAβ) peptides affect glucose transport at the blood-brain barrier (BBB), the primary portal for glucose entry into the brain. We demonstrated that [F]-fluorodeoxyglucose (FDG) uptake is reduced in sAβ overproducing APP,PS1 transgenic mice compared to wild-type mice. Moreover, the influx rate of FDG decreased in sAβ40 or sAβ42 pre-infused mice, highlighting the inhibitory effect of sAβ peptides on glucose transport at the BBB. Consistently, the expression of GLUT1, the primary glucose transporter at the BBB, is reduced in polarized human cerebral microvascular endothelial cell (hCMEC/D3) monolayers upon exposure to sAβ peptides and in Aβ-laden cerebral vasculature in vivo. The study further examined the influence of sAβ on the insulin-AKT pathway, known to regulate glucose uptake through modulation of thioredoxin-interacting protein (TXNIP) expression. Results showed that sAβ peptides suppress AKT phosphorylation and reduce GLUT1 expression by upregulating TXNIP levels in hCMEC/D3 monolayers. Co-incubation of resveratrol with sAβ peptides reduced TXNIP expression and rectified reductions in GLUT1 expression. In summary, toxic sAβ impairs BBB glucose transport by disrupting the insulin/AKT/TXNIP axis.
与阿尔茨海默病（AD）患者认知能力下降相关的大脑葡萄糖摄取和代谢紊乱的分子机制，目前仅得到部分理解。本研究调查了可溶性淀粉样β蛋白（sAβ）肽如何影响血脑屏障（BBB）处的葡萄糖转运，血脑屏障是葡萄糖进入大脑的主要通道。我们证明，与野生型小鼠相比，过量产生sAβ的APP、PS1转基因小鼠中[F] - 氟脱氧葡萄糖（FDG）摄取减少。此外，预先注入sAβ40或sAβ42的小鼠中FDG的流入速率降低，突出了sAβ肽对血脑屏障处葡萄糖转运的抑制作用。同样，在暴露于sAβ肽的极化人脑血管内皮细胞（hCMEC/D3）单层以及体内载有Aβ的脑血管中，血脑屏障处主要的葡萄糖转运蛋白GLUT1的表达降低。该研究进一步考察了sAβ对胰岛素 - AKT途径的影响，已知该途径通过调节硫氧还蛋白相互作用蛋白（TXNIP）的表达来调控葡萄糖摄取。结果显示，sAβ肽通过上调hCMEC/D3单层中TXNIP的水平来抑制AKT磷酸化并降低GLUT1的表达。白藜芦醇与sAβ肽共同孵育可降低TXNIP的表达，并纠正GLUT1表达的降低。总之，有毒的sAβ通过破坏胰岛素/AKT/TXNIP轴损害血脑屏障的葡萄糖转运。
