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-beta (A beta) peptides, and in delivering essential nutrients to the brain, like insulin. In Alzheimer's disease (AD) brain, increased A beta 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 A beta and insulin trafficking at the BBB. Following intravenous infusion of an IGF1R/IR kinase inhibitor (AG1024) in wild-type mice, the BBB trafficking of I-125 radiolabeled A beta peptides and insulin was assessed by dynamic SPECT/CT imaging. The brain efflux of [I-125]iodo-A beta 42 decreased upon AG1024 treatment. Additionally, the brain influx of [I-125]iodoinsulin, [I-125]iodo-A beta 42, [I-125]iodo-A beta 40, and [I-125]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 [I-125]iodoinsulin, [I-125]iodo-A beta 42, and [I-125]iodo-A beta 40 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 A beta and insulin trafficking receptors (LRP-1 and IR-beta). These findings reveal that insulin signaling differentially regulates the BBB trafficking of A beta 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 A beta accumulation while decreasing insulin delivery to the brain, which has been linked to the progression of cognitive decline in AD.