Effects of APOE Isoforms on Brain Insulin Signaling and Energy Metabolism in Alzheimer’s Disease

Project Summary

APOE ε4 gene is the strongest genetic risk factor for late-onset AD by modulating amyloid-β (Aβ)-dependent and independent pathways. We have recently demonstrated that in the absence of Aβ, apoE4 transgenic mice showed impaired cerebral insulin signaling with aging. In this project, we plan to examine how Aβ and apoE4 synergistically impair brain insulin signaling, and whether this effect could be rescued by brain administration of insulin. We have two specific Aims:

Aim 1. To examine how Aβ and apoE4 synergistically suppress brain insulin signaling and glucose metabolism. We will assess brain insulin signaling and glucose metabolism in amyloid model mice expressing human APOE genes. In vivo microdialysis technique will be used to measure Aβ, apoE, and glucose in brain interstitial fluid.

Aim2. To examine whether brain administration of insulin rescues Aβ and apoE4-related impairments in brain insulin signaling, glucose metabolism, brain activity, and cognition. We will administrate insulin (short-acting or long-acting form) acutely or chronically via intranasal delivery, and evaluate brain insulin signaling, glucose metabolism, cerebral blood flow, brain activity, and behaviors.

With the recent failure of clinical trials that have targeted the Aβ pathway alone, there is an urgent need to develop novel therapeutic methods to treat AD. As the ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD among its three polymorphic alleles (ε2, ε3, and ε4), it is an attractive alternative target for AD therapy. A recent Phase II clinical trial with insulin nasal spray in AD patients has yielded positive results in preventing cognitive decline. It is interesting that APOE genotype status appears to modulate the cognitive response to insulin in these clinical trials. Thus, there is an urgent need to understand the function and regulation of brain insulin signaling and glucose metabolism in preclinical models. Using amyloid mouse model expressing different human APOE genes, we will assess how Aβ and apoE4 synergistically contribute to impaired insulin signaling and glucose pathway; and examine whether a restoration of insulin signaling allows a rescue of Aβ and apoE4-related AD phenotypes. Our proposed study should provide essential knowledge regarding how restoring insulin signaling in AD brain helps with improving cognition, and direct the therapeutic strategy concerning how AD patients with different APOE isoforms should be treated.