The most important genetic risk factor for Alzheimer's disease (AD) is the APOE gene. APOE encodes the apolipoprotein E (apoE) protein, the main apolipoprotein in the central nervous system (CNS). ApoE interacts with the family of low density lipoprotein receptors, and these apoE receptors are expressed by neurons and glia. Thus, apoE receptors regulate apoE metabolism and mediate the effects of apoE on neuronal signaling, APP processing, neurotoxicity, and synaptic function. The goal of this Program is to take advantage of the overlapping interests and diverse expertise of five scientists examining the biology of apoE and apoE receptors in the CNS.
The Aims of this Program are to define the expression and function of apoE receptors in the CNS, and how their functions are regulated by the three apoE isoforms and cellular proteolytic events. These projects also include an examination of the generation and function of soluble receptors. In Project 1, Dr. LaDu will examine how apoE receptors and beta-amyloid peptide mediate the metabolism of the 3 human apoE isoforms. In Project 2, Dr. Estus will test whether genetic variations within apoE receptor genes alter their functions and define whether these variations affect the risk of AD. In Project 3, Dr. Bu will define factors that affect the trafficking and processing of one of these receptors, LRP, and determine how LRP affects the amyloid precursor protein. In Project 4, Dr. Rebeck will examine another brain apoE receptor, ApoER2, and determine how its processing is regulated, and define the fate of soluble apoE receptors. In Project 5, Dr. Weeber will determine the mechanisms of apoE-dependent modulation of synaptic plasticity and in vivo effects of apoE receptor activation on neurobehavior and neuroplasticity. THE CORES INCLUDE: A) Administrative Core (for fiscal management, maintaining good communications between the five sites and overseeing a yearly symposium on apoE and apoE receptors);B) Molecular Cell Biology Core (for conducting standardized assays of apoE, apoE receptors, and Abeta, for developing, characterizing and distributing new common reagents, and for generating new transgenic mouse models as part of this Program);and C) Transgenic Core (all mice are maintained at Taconic, for distributing transgenic mouse models of AD and mice with altered levels of apoE receptors). This Program will thus provide new and valuable information about how apoE and apoE receptors affect the pathogenesis of Alzheimer's disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-4 (O5))
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Petanceska, Suzana
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University of Illinois at Chicago
Anatomy/Cell Biology
Schools of Medicine
United States
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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

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