ApoE and cerebral insulin: Trafficking, receptors, and resistance

Abstract

Central nervous system (CNS) insulin resistance is associated with Alzheimer's disease (AD). In addition, the apolipoprotein E4 (apoE4) isoform is a risk factor for AD. The connection between these two factors in relation to AD is being actively explored. We summarize this literature with a focus on the transport of insulin and apoE across the blood-brain barrier (BBB) and into the CNS, the impact of apoE and insulin on the BBB, and the interactions between apoE, insulin, and the insulin receptor once present in the CNS. We highlight how CNS insulin resistance is apparent in AD and potential ways to overcome this resistance by repurposing currently approved drugs, with apoE genotype taken into consideration as the treatment response following most interventions is apoE isoform-dependent. This review is part of a special issue focusing on apoE in AD and neurodegeneration.

Keywords: Alzheimer's disease; Amyloid beta; Apolipoprotein E; Blood-brain barrier; Central nervous system insulin; Insulin receptor.

Figure 1.. Relation of CNS Levels and CNS/Blood Ratios to Blood Levels: Theoretical Data.

This figure illustrates how the nonlinear relation between CNS and Blood levels can result in increasing blood levels being accompanied by both increasing CNS levels and decreasing CNS/Blood Ratios. A less efficient transporter would shift the CNS curve downward/to the right so that CNS levels will be lower for any given Blood level.

Figure 2.. Levels of Insulin Resistance.

Glucose uptake is stimulated by tissues containing GLUT-4 (primarily muscle, liver, and adipose tissue), but not by those containing GLUT-1, 3, or 5 (such as brain endothelial cells, astrocytes, neurons, and microglia). Points of Insulin Resistance: 1) Insulin resistance at GLUT-4 dependent peripheral tissues results in hyperglycemia, unless countered by an elevation in insulin levels. 2) Brain endothelial cells respond to insulin in ways other than glucose uptake. 3) The insulin transporter at the BBB has a rate that can be modified; a decreased transport rate can result in less insulin action in the brain. 4) Insulin receptor resistance can occur on CNS cells.

Figure 3.. Developmental origin of Insulin Resistance, Mild Cognitive Impairment (MCI), and AD.

Genetic and environmental risk factors contribute to the detrimental brain impact that can lead to development of MCI and AD. Efficacy of intervention through either medication or life-style changes is also often apoE isoform-dependent.