Elizabeth Rhea, United States of America
University of Washington MedicinePresenter of 2 Presentations
IMPACT OF APOE ISOFORM, SEX, AND DIET ON INSULIN TRANSPORT INTO THE MOUSE CNS
Abstract
Aims
The effects of central nervous system (CNS) insulin on cognition and metabolism are modified by apolipoprotein E (apoE) isoform, sex, and dietary lipids (e.g, a high-fat diet (HFD)). In humans, there are three major apoE isoforms, E2, E3, and E4. Compared to E3, E4 is the major genetic risk factor for the onset of Alzheimer’s disease (AD). Insulin in the CNS is primarily derived from blood insulin, which is transported across the blood-brain barrier (BBB). An alternative way to increase brain insulin levels is by delivering insulin via the intranasal (INL) route, bypassing the BBB and limiting the glucose regulatory effects of insulin. Mild cognitive impairment (MCI) and AD female and male patients with E4 and female patients without E4 respond less well to INL insulin, suggesting an exaggerated deficiency in insulin’s action. Our studies show how transport of insulin across the BBB or following INL delivery may be altered.
Methods
Using radiolabeled insulin, we measured the pharmacokinetics across the BBB in addition to measuring the distribution following INL delivery in E3 and E4 targeted-replacement mice.
Results
Insulin BBB transport varies regionally and the rate and level of vascular binding varies due to apoE isoform, sex, and diet. Following INL delivery, insulin appears throughout the brain within 5 min and remains elevated up to 60 min later.
Conclusions
These results suggest that these three risk factors for AD (apoE isoform, sex, and diet) play a role in regulating insulin transport into the CNS.
LIVE DISCUSSION
