The effects of peripheral and central high insulin on brain insulin signaling and amyloid-β in young and old APP/PS1 mice

Hyperinsulinemia is a risk factor for late-onset Alzheimer’s disease (AD). In vitro experiments describe potential connections between insulin,insulin signaling,and amyloid-β (Aβ),but in vivo experiments are needed to validate these relationships under physiological conditions. First,we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young,awake,behaving APP_swe/PS1_dE9 transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain,ISF,or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia,despite detecting increased signaling in the muscle. Next,we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased,but ISF Aβ was unchanged by central insulin administration. Finally,to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology,we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ,whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling,with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice,independent of neuronal insulin signaling.