APOE4 is the strongest genetic risk factor for Alzheimer's disease (AD); however, how apoE4 predisposes people for the risk for AD is still not clear. Clinical studies have shown that APOE4 carriers, both as healthy adults or with dementia, have lower cerebral glucose metabolism and increased neuroinflammation, conditions that are also common in individuals with diabetes. Interestingly, diabetes and impaired insulin signaling are linked to the pathogenesis of AD. Supporting these, a recent clinical trial with insulin intranasal spray in AD patients has yielded positive results in preventing cognitive decline and this has led to a new national plan for a Phase II/III trial. Thus, there is an urgent need to understand the function and regulation of brain insulin signaling and glucose metabolism in preclinical models. In the previous funding cycle and during the preliminary stage of this project, we found that apoE and its major receptor LRP1 regulate the metabolism of both lipid and glucose in the brain. Specifically, using in vivo microdialysis techniques, we found that brain glucose metabolism is impaired in APOE4-targeted replacement (TR) mice and in Lrp1 neuronal knockout mice. We also found that LRP1 interacts with insulin receptor (IR) and regulates insulin signaling and glucose metabolism in a manner that depends on the function of glucose transporter 4 (GLUT4). Impaired insulin signaling and chronic neuroinflammation were further exacerbated in the APOE4 mice by either amyloid- (A) pathology or a loss of neuronal LRP1. Thus, our goal for this renewal project is to study the molecular and cellular mechanisms by which apoE4 synergizes with pro-inflammatory cytokines and A to impair neuronal insulin signaling and glucose metabolism and test whether a restoration of insulin signaling in APOE4-TR mice allows a rescue of APOE4-related AD phenotypes. We hypothesize that apoE4 impairs neuronal insulin signaling and glucose metabolism in a manner that depends on the functions of apoE receptor LRP1 and glucose transporters, and that neuroinflammation and A further exacerbate these events in aging and AD. We propose three Specific Aims to test our hypothesis.
In Aim 1, we plan to dissect the mechanisms by which apoE4 impairs neuronal insulin signaling and glucose metabolism in vitro in neurons, in vivo in APOE-TR mice, and in human brains.
In Aim 2, we will examine how pro-inflammatory cytokines and A synergize with apoE4 in reducing neuronal insulin signaling and glucose metabolism.
In Aim 3, we plan to test whether brain administration of insulin or insulin-sensitizing drug metformin, or a restoration of apoE4 expression and lipidation rescues impaired glucose metabolism, reduces apoE4-associated neuroinflammation, and improve synaptic functions and cognition. These studies will not only address the underlying mechanisms of impaired insulin signaling and glucose metabolism in APOE4 carriers and AD patients but will also test therapeutic potentials targeting insulin and apoE pathways.

Public Health Relevance

Diabetes and Alzheimer's disease (AD) are growing health concerns that affect a large population of our aging society. Interestingly, diabetes is also a ris factor for AD. The strongest genetic risk factor for AD is APOE4, which promotes conditions common to diabetes and AD, including impaired insulin signaling and chronic inflammation. Thus, the goal of this project is to reveal how APOE4 synergizes with other pathogenic pathways to increase the risk for AD and how we can target these pathways for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG035355-11
Application #
9741009
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Petanceska, Suzana
Project Start
2009-12-01
Project End
2020-05-31
Budget Start
2019-06-15
Budget End
2020-05-31
Support Year
11
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Zhao, Na; Liu, Chia-Chen; Qiao, Wenhui et al. (2018) Apolipoprotein E, Receptors, and Modulation of Alzheimer's Disease. Biol Psychiatry 83:347-357
Ogaki, Kotaro; Martens, Yuka A; Heckman, Michael G et al. (2018) Multiple system atrophy and apolipoprotein E. Mov Disord 33:647-650
Kang, S S; Ren, Y; Liu, C-C et al. (2018) Lipocalin-2 protects the brain during inflammatory conditions. Mol Psychiatry 23:344-350
Zhao, Na; Liu, Chia-Chen; Van Ingelgom, Alexandra J et al. (2018) APOE ?2 is associated with increased tau pathology in primary tauopathy. Nat Commun 9:4388
Tachibana, Masaya; Yamazaki, Yu; Liu, Chia-Chen et al. (2018) Pericyte implantation in the brain enhances cerebral blood flow and reduces amyloid-? pathology in amyloid model mice. Exp Neurol 300:13-21
Zhong, Li; Zhang, Zhen-Lian; Li, Xinxiu et al. (2017) TREM2/DAP12 Complex Regulates Inflammatory Responses in Microglia via the JNK Signaling Pathway. Front Aging Neurosci 9:204
Liu, Chia-Chen; Zhao, Na; Fu, Yuan et al. (2017) ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96:1024-1032.e3
Wojtas, Aleksandra M; Kang, Silvia S; Olley, Benjamin M et al. (2017) Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proc Natl Acad Sci U S A 114:E6962-E6971
Zheng, Honghua; Jia, Lin; Liu, Chia-Chen et al. (2017) TREM2 Promotes Microglial Survival by Activating Wnt/?-Catenin Pathway. J Neurosci 37:1772-1784
Nielsen, Henrietta M; Chen, Kewei; Lee, Wendy et al. (2017) Peripheral apoE isoform levels in cognitively normal APOE ?3/?4 individuals are associated with regional gray matter volume and cerebral glucose metabolism. Alzheimers Res Ther 9:5

Showing the most recent 10 out of 76 publications