Regulating ApoE’s Effects on Insulin Signaling and Energy Metabolism in the Alzheimer’s Brain

Na Zhao, MD, PhD
Mayo Clinic Jacksonville (Jacksonville, FL)


Guojun Bu, PhD
Mayo Clinic Jacksonville (Jacksonville, FL)
Year Awarded:
Grant Duration:
July 1, 2018 to June 30, 2020
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Postdoctoral Fellowship
Award Region:
US Southeastern
Na Zhao, MD, PhD

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


Studies show that having the apolipoprotein E4 (APOE4) gene increases a person's risk for Alzheimer's diseases (AD). The persons who have AD and/or the APOE4 gene have problems with obtaining energy in their brain. Insulin is a drug that could help with the process of breaking down substances in the cells to obtain energy. Thus we would like to use animal models to look at whether insulin can rescue the brain energy in the animals that have AD and/or APOE4 gene. Our findings will be very useful in understanding how apoE4 impairs brain health and how we can use insulin as an effective treatment for AD.


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.

About the Researcher

I earned my MD degree, MS degree, completed the neurology residency training, and then worked at a memory clinic in Shanghai, China for four years as a neurologist. In the interim, I also earned my Ph. degree at Fudan University in China, gaining research experience in the neurodegenerative disease field. Since joining Dr. Guojun Bu’s lab at Mayo Clinic in Jacksonville, FL, as a research fellow three years ago, I have gained further research training in apoE biology and pathobiology with techniques spanning biochemistry, cell biology, and animal modeling. These learning and working experiences in both clinical and lab settings helped me to appreciate the interconnection of science and medicine. I have a deep passion to help the suffering patients through innovative research with a specific interest in translational medicine. My research interest is to define how insulin signaling and glucose metabolism associate with the etiology of Alzheimer’s disease (AD), and how APOE gene and apoE receptors modulate the pathological processing of AD, using both in vivo and in vitro approaches. In particular, my current research goal is to understand how amyloid β and apoE4 synergistically affect neuronal insulin signaling and glucose metabolism, and the mechanistic basis of apoE isoform-related differences upon insulin treatments, in order to design individualized therapies for AD based on APOE genotype status. 

Personal Story

As a physician, I understand that the art of medicine is to cure sometimes, to relieve often, to comfort always--from Dr. Edward Trudeau in the 1800s. This is the frustration of modern medicine. As a researcher, I believe we will find a way to cure Alzheimer’s disease (AD) someday. I was lucky that my mentor, Dr. Bu, was happy to accept me into his lab since 2014 and trained me towards becoming an independent scientist in the Alzheimer’s research field! I feel excited when I find that several Phase II clinical trials of intranasal insulin showed a beneficial role on cognitive function in Alzheimer’s patients, and the Phase III clinical trials are currently ongoing. Although insulin is a mature medicine for the treatment of Type II diabetes, the exact functions of insulin in the brain are not yet clear. So my current research goal is to understand the effects of intranasal insulin on glucose metabolism and brain functions. I am grateful to the donors of BrightFocus Foundation for supporting our research on discovering the role of insulin in the brain, using preclinical models which will help the corresponding design of clinical trials and therapeutic strategy in AD.


Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol. 2019 Sep;15(9):501-518. doi: 10.1038/s41582-019-0228-7. Epub 2019 Jul 31. Review. PubMed PMID: 31367008. PubMed Icon Google Scholar Icon

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