Insulin Signaling Differentially Regulates the Trafficking of Insulin and Amyloid Beta Peptides at the Blood-Brain Barrier

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.