The major goal of this proposal is to develop and validate therapeutic strategies targeting apolipoprotein E (APOE) gene with a specific focus on reducing the pathogenic effects of APOE4, the strongest genetic risk factor for late-onset Alzheimer's disease (AD). In our previous funding cycle, we have developed cell type- specific and inducible mouse models expressing human APOE3 or APOE4. Using these models, we have shown that expression of APOE4 in the brain or periphery leads to impairments in synaptic functions and enhancement of amyloid pathologies, whereas expression of APOE3 is either neutral or beneficial. The effects of peripherally expressed apoE4 on brain cognition and AD-related pathologies are particular exciting as we for the first time were able to separate the effects of brain and peripheral apoE4; the latter appears to modulate brain functions at least partially by compromising vascular integrity and function. Those findings also provide strong scientific premise that shifting apoE isoform status from the harmful apoE4 to neutral/beneficial apoE3 (or perhaps the protective apoE2) only in the periphery can reduce the risk and/or slow the progression of AD for APOE4 carriers in particular the APOE4 homozygotes. For this renewal application, we plan to perform preclinical testing using genetic or plasma exchange approaches. Our central hypothesis is that shifting apoE isoforms in the periphery from apoE4 to apoE3 can rescue AD-related pathology and cognitive decline by improving vascular function and promoting protective immune responses. We plan to test our hypothesis through three specific aims:
In Aim 1, we plan to examine how peripheral APOE3 expression by the liver in the background of APOE4 genotype at different ages and different stages of the amyloid pathology impacts AD- related pathways. Peripheral apoE3 expression will be achieved by breeding our conditional APOE3 mouse model with Albumin-Cre (Alb-Cre) mice in the background of APOE4-targeted replacement (TR) mice. Effects on synaptic functions, behaviors, and AD-related pathology will be examined at different ages and different stages of amyloid pathology in both male and female mice. Single cell RNA sequencing studies will be carried out to uncover new pathways and networks impacted by APOE genotype changes.
In Aim 2, we plan to address how macrophage APOE3 expression driven by LysM-Cre in the background of APOE4-TR impacts AD-related pathologies and pathways.
In Aim 3, we will test whether blood exchange from apoE4 to apoE3 in APOE4-TR mice through parabiosis or infusion of plasma from young APOE3-TR mice can rescue AD-related pathologies and pathways. Successful completion of these studies should provide strong preclinical rationale and guidance for designing human clinical trials by modulating peripheral apoE isoforms, offering novel, individualized therapeutic strategies based on APOE genotype.

Public Health Relevance

Alzheimer's disease (AD) is the leading cause of dementia in the elderly affecting a large population of our aging society, yet we still do not have an effective way to treat this devastating disease. Towards this, the goal of this project is to establish and test a new therapeutic target, apolipoprotein E (APOE), in particular the harmful form of APOE4 that increases AD risk by promoting several pathogenic pathways. Genetic and plasma exchange approaches will be employed to test whether introducing the beneficial APOE3 in APOE4 animals can rescue AD-related phenotypes and pathologies for an eventual goal of developing APOE targeted, individualized therapies to treat AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG046205-06
Application #
9684763
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Dibattista, Amanda
Project Start
2013-09-30
Project End
2023-11-30
Budget Start
2019-01-15
Budget End
2019-11-30
Support Year
6
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
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
Liu, Chia-Chen; Zhao, Na; Fu, Yuan et al. (2017) ApoE4 Accelerates Early Seeding of Amyloid Pathology. Neuron 96:1024-1032.e3
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
Rogers, Justin T; Liu, Chia-Chen; Zhao, Na et al. (2017) Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice. Neurobiol Aging 53:112-121
Liu, Chia-Chen; Hu, Jin; Zhao, Na et al. (2017) Astrocytic LRP1 Mediates Brain A? Clearance and Impacts Amyloid Deposition. J Neurosci 37:4023-4031
Zhao, Na; Liu, Chia-Chen; Van Ingelgom, Alexandra J et al. (2017) Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes. Neuron 96:115-129.e5

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