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 #
5P01AG030128-02
Application #
8103834
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$254,061
Indirect Cost
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Brown, Christopher A; Jiang, Yang; Smith, Charles D et al. (2018) Age and Alzheimer's pathology disrupt default mode network functioning via alterations in white matter microstructure but not hyperintensities. Cortex 104:58-74
Gold, Brian T; Brown, Christopher A; Hakun, Jonathan G et al. (2017) Clinically silent Alzheimer's and vascular pathologies influence brain networks supporting executive function in healthy older adults. Neurobiol Aging 58:102-111
Brown, Christopher A; Johnson, Nathan F; Anderson-Mooney, Amelia J et al. (2017) Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease. Neuroimage Clin 13:106-115
Di Battista, Amanda M; Heinsinger, Nicolette M; Rebeck, G William (2016) Alzheimer's Disease Genetic Risk Factor APOE-?4 Also Affects Normal Brain Function. Curr Alzheimer Res 13:1200-1207
Yang, Longyu; Liu, Chia-Chen; Zheng, Honghua et al. (2016) LRP1 modulates the microglial immune response via regulation of JNK and NF-?B signaling pathways. J Neuroinflammation 13:304
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
Fu, Yuan; Zhao, Jing; Atagi, Yuka et al. (2016) Apolipoprotein E lipoprotein particles inhibit amyloid-? uptake through cell surface heparan sulphate proteoglycan. Mol Neurodegener 11:37
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
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
Ghura, Shivesh; Tai, Leon; Zhao, Ming et al. (2016) Arabidopsis thaliana extracts optimized for polyphenols production as potential therapeutics for the APOE-modulated neuroinflammation characteristic of Alzheimer's disease in vitro. Sci Rep 6:29364

Showing the most recent 10 out of 159 publications