血脑屏障(BBB)有助于清除大脑中的有毒代谢物,如淀粉样蛋白-β(Aβ)肽,向大脑提供必需的营养,比如胰岛素.在阿尔茨海默病(AD)的大脑,Aβ水平升高与胰岛素水平降低平行,其在BBB处伴有胰岛素信号传导缺陷。因此,我们研究了胰岛素样生长因子和胰岛素受体(IGF1R和IR)信号传导对BBB处Aβ和胰岛素运输的影响。在野生型小鼠中静脉输注IGF1R/IR激酶抑制剂(AG1024)后,通过动态SPECT/CT成像评估125I放射性标记的Aβ肽和胰岛素的BBB运输。在AG1024处理后,[125I]碘-Aβ42的脑流出减少。此外,大脑中[125I]碘胰岛素的涌入,[125I]碘-Aβ42,[125I]碘-Aβ40和[125I]碘-BSA(BBB完整性标记)降低,增加,不变,不变,分别,在AG1024治疗。使用体外BBB细胞模型进行随后的机理研究。[125I]碘胰岛素的细胞摄取,[125I]碘-Aβ42和[125I]碘-Aβ40减少,增加,不变,分别,在AG1024治疗。Further,AG1024降低了胰岛素信号传导激酶(Akt和Erk)的磷酸化以及Aβ和胰岛素运输受体(LRP-1和IR-β)的膜表达。这些发现揭示了胰岛素信号传导差异调节Aβ肽和胰岛素的BBB运输。此外,IGF1R和IR信号传导缺陷,正如在II型糖尿病和AD患者的大脑中观察到的那样,预计会增加Aβ积累,同时减少胰岛素向大脑的输送,这与AD认知衰退的进展有关。
The blood-brain barrier (BBB) is instrumental in clearing toxic metabolites from the brain, such as amyloid-β (Aβ) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer\'s disease (AD) brain, increased Aβ levels are paralleled by decreased insulin levels, which are accompanied by insulin signaling deficits at the BBB. Thus, we investigated the impact of insulin-like growth factor and insulin receptor (IGF1R and IR) signaling on Aβ and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of 125I radiolabeled Aβ peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [125I]iodo-Aβ42 decreased upon AG1024 treatment. Additionally, the brain influx of [125I]iodoinsulin, [125I]iodo-Aβ42, [125I]iodo-Aβ40, and [125I]iodo-BSA (BBB integrity marker) was decreased, increased, unchanged, and unchanged, respectively, upon AG1024 treatment. Subsequent mechanistic studies were performed using an in vitro BBB cell model. The cell uptake of [125I]iodoinsulin, [125I]iodo-Aβ42, and [125I]iodo-Aβ40 was decreased, increased, and unchanged, respectively, upon AG1024 treatment. Further, AG1024 reduced the phosphorylation of insulin signaling kinases (Akt and Erk) and the membrane expression of Aβ and insulin trafficking receptors (LRP-1 and IR-β). These findings reveal that insulin signaling differentially regulates the BBB trafficking of Aβ peptides and insulin. Moreover, deficits in IGF1R and IR signaling, as observed in the brains of type II diabetes and AD patients, are expected to increase Aβ accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.