In the past decade, apoE has emerged as one of the best validated risk factors for late-onset, sporadic Alzheimer's disease (AD). Despite a great deal of research that has significantly improved understanding of apoE and its receptors, the mechanism by which apoE genotype influences an individual's predisposition to AD remains unknown. We know that specific lipoprotein receptors are essential in maintaining normal synaptic plasticity and learning and memory processes in the adult mouse hippocampus. The ligand- receptor interaction between apoE and its receptors is well poised in the molecular framework of the synapse to have broad implications for both normal cognitive processes and the perturbations observed in early AD. The overall hypothesis of this proposal states that that apoE acts as an isoform-specific signaling ligand to modulate neuronal synaptic plasticity and hippocampal-dependent memory formation, and is susceptible to changes in fi amyloid accumulation. The different apoE isoforms, the ligand reelin and the four prominent apoE receptors that bind these ligands adds an exceedingly complicated level of complexity to this system. This proposal is designed to better understand four important aspects of apoE signaling and apoE receptor function: 1) The circumstances that influence apoE receptor processing. 2) The mechanisms that underlie apoE-dependent changes in synaptic function and memory formation. 3) The interactions between specific apoE receptors and apoE isoforms in receptor signaling and processing. 4) The role of apoE isoform signaling and apoE receptor processing in the pathological processes associated with Alzheimer's disease. These studies will be the first to identify interactions of apoE isoforms to specific receptors and how those interactions can affect CNS function. These insights will be valuable in assessing AD risk, formulating new treatment strategies for AD, identifying potential therapeutic drug targets for the management of AD and provide insight into other age-related disorders involving the lipoprotein receptor system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG030128-04
Application #
8380117
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$212,950
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Luo, Jia; Lee, Sue H; VandeVrede, Lawren et al. (2016) A multifunctional therapeutic approach to disease modification in multiple familial mouse models and a novel sporadic model of Alzheimer's disease. Mol Neurodegener 11:35
DiBattista, Amanda M; Dumanis, Sonya B; Newman, Joshua et al. (2016) Identification and modification of amyloid-independent phenotypes of APOE4 mice. Exp Neurol 280:97-105
Cacciottolo, Mafalda; Christensen, Amy; Moser, Alexandra et al. (2016) The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice. Neurobiol Aging 37:47-57
Fu, Yuan; Zhao, Jing; Atagi, Yuka et al. (2016) Apolipoprotein E lipoprotein particles inhibit amyloid-β uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener 11:37
Tai, Leon M; Thomas, Riya; Marottoli, Felecia M et al. (2016) The role of APOE in cerebrovascular dysfunction. Acta Neuropathol 131:709-23
Teter, Bruce; LaDu, Mary Jo; Sullivan, Patrick M et al. (2016) Apolipoprotein E isotype-dependent modulation of microRNA-146a in plasma and brain. Neuroreport 27:791-5
Yang, Longyu; Liu, Chia-Chen; Zheng, Honghua et al. (2016) LRP1 modulates the microglial immune response via regulation of JNK and NF-κB signaling pathways. J Neuroinflammation 13:304
Casey, Caroline S; Atagi, Yuka; Yamazaki, Yu et al. (2015) Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway. J Biol Chem 290:14208-17
Zhong, Li; Chen, Xiao-Fen; Zhang, Zhen-Lian et al. (2015) DAP12 Stabilizes the C-terminal Fragment of the Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) and Protects against LPS-induced Pro-inflammatory Response. J Biol Chem 290:15866-77
Liu, De-shan; Pan, Xiao-dong; Zhang, Jing et al. (2015) APOE4 enhances age-dependent decline in cognitive function by down-regulating an NMDA receptor pathway in EFAD-Tg mice. Mol Neurodegener 10:7

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