Type II diabetes has emerged as a major risk factor for Alzheimer’s disease, but the underlying mechanisms are poorly understood. Here, we investigated insulin and amyloid-beta (Aβ) peptide trafficking at the blood-brain barrier (BBB) in healthy vs. diabetes (high-fat diet) and Alzheimer’s (APP/PS1 transgenic) mice. Following systemic injection of radiolabeled protein, the brain accumulation was monitored by dynamic SPECT/CT imaging. Compared to healthy mice, both the diabetes and Alzheimer’s mice demonstrated decreased brain uptake of insulin and increased uptake of Aβ42. Reverse-phase protein array performed on harvested brain microvessels revealed global disruptions to insulin signaling pathways in both disease models. The reduced expression/activity of key insulin signaling kinases was confirmed by western blot. In healthy mice, infusion with an insulin signaling inhibitor decreased the brain uptake of insulin and increased that of Aβ42. Thus, during both diabetes and Alzheimer’s disease, insulin signaling deficits at the BBB differentially impact the brain uptake of insulin and Aβ42 in a manner that is expected to exacerbate Alzheimer’s pathology.
Interpret the role of insulin signaling in BBB dysfunction during Alzheimer's disease
Relate the BBB trafficking of insulin and Aβ peptides
Appreciate the significance of insulin resistance as a target for Alzheimer's disease