Insulin differentially affects the distribution kinetics of amyloid beta 40 and 42 in plasma and brain

Impaired brain clearance of amyloid-beta peptides (A beta) 40 and 42 across the blood-brain barrier (BBB) is believed to be one of the pathways responsible for Alzheimer's disease (AD) pathogenesis. Hyperinsulinemia prevalent in type II diabetes was shown to damage cerebral vasculature and increase A beta accumulation in AD brain. However, there is no clarity on how aberrations in peripheral insulin levels affect A beta accumulation in the brain. This study describes, for the first time, an intricate relation between plasma insulin and A beta transport at the BBB. Upon peripheral insulin administration in wild-type mice: the plasma clearance of A beta 40 increased, but A beta 42 clearance reduced; the plasma-to-brain influx of A beta 40 increased, and that of A beta 42 reduced; and the clearance of intracerebrally injected A beta 40 decreased, whereas A beta 42 clearance increased. In hCMEC/D3 monolayers (in vitro BBB model) exposed to insulin, the luminal uptake and luminal-to-abluminal permeability of A beta 40 increased and that of A beta 42 reduced; the abluminal-to-luminal permeability of A beta 40 decreased, whereas A beta 42 permeability increased. Moreover, A beta cellular trafficking machinery was altered. In summary, A beta 40 and A beta 42 demonstrated distinct distribution kinetics in plasma and brain compartments, and insulin differentially modulated their distribution. Cerebrovascular disease and metabolic disorders may disrupt this intricate homeostasis and aggravate AD pathology.