ApoE receptors mediate many of the functions of apoE in the CNS;including endocytosis of lipoproteins, activation of kinase signaling pathways, and modulation of synaptic signaling and glial activation. One important aspect of apoE receptor biology is its shedding from the cell via regulated cleavage mechanisms. In this project, we will focus on one of these apoE receptors, ApoER2.
In Aim 1, we will test how proteolytic enzymes generate soluble receptors and cytoplasmic fragments, analyzing ADAMs and BACE. We will determine the mechanism of these cleavages, testing whether they are altered by the alternatively spliced O- linked glycosylation domain of ApoER2 and inhibited by the endogenous metalloproteinase inhibitor, TIMP-3. We hypothesize that the proteases responsible for APR cleavage also act on apoE receptors.
In Aim 2, we will focus on the regulation of these cleavage events. We will test how cytoplasmic adaptor proteins (FE65, Dab-1, SNX-17), influence trafficking of ApoER2, and how ligand binding (specifically apoE isoforms) affect receptor metabolism. We will examine the role shedding plays in the functions of ApoER2 in endocytosis and signaling, inlcuding mechanisms of neurotoxicity.
In Aim 3, we will test how secreted apoE receptors are cleared, examining several possible mediators of endocytosis. Through these three aims, we will define the production, function, and clearance of soluble ApoER2, and how the shedding process affects the functions of full-length ApoER2.
In Aim 4, we will examine the connections between ApoER2 and APP, using primary neurons and genetically modified mice. We will test how ligands (apoE-lipoproteins) affect ApoER2 proteolysis in vivo, and how soluble and full length ApoER2 affect AH plaque formation. We hypothesizethat because APP and apoE receptors share ligands, adaptor proteins, and proteolytic pathways, alteration of receptors such as ApoER2 have important effects on APP trafficking and proteolysis in vivo. We will work in concert with the other projects to progress each of these aims: Project 1for understanding how physiologically relevant forms of human apoE isoforms affect ApoER2 function including neurotoxicity; Project 2 for analysis of receptor splice variants;Project 3 for analysis of ApoER2 trafficking and processing; and Project 5 for determining the effects of ApoER2 on neuronal signaling and APP processing in vivo. Overall, these studies will examine the functional effects of apoE isoforms via ApoER2 in the CNS.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-4)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Illinois at Chicago
United States
Zip Code
Zhao, Jing; Fu, Yuan; Liu, Chia-Chen et al. (2014) Retinoic acid isomers facilitate apolipoprotein E production and lipidation in astrocytes through the retinoid X receptor/retinoic acid receptor pathway. J Biol Chem 289:11282-92
Liu, Chia-Chen; Kanekiyo, Takahisa; Roth, Barbara et al. (2014) Tyrosine-based signal mediates LRP6 receptor endocytosis and desensitization of Wnt/?-catenin pathway signaling. J Biol Chem 289:27562-70
Divekar, Shailaja D; Burrell, Teal C; Lee, Jennifer E et al. (2014) Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2. J Biol Chem 289:15894-903
Tamboli, Irfan Y; Heo, Dongeun; Rebeck, G William (2014) Extracellular proteolysis of apolipoprotein E (apoE) by secreted serine neuronal protease. PLoS One 9:e93120
Tai, Leon M; Koster, Kevin P; Luo, Jia et al. (2014) Amyloid-? pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. J Biol Chem 289:30538-55
Kunzler, Jacqueline; Youmans, Katherine L; Yu, Chunjiang et al. (2014) APOE modulates the effect of estrogen therapy on A* accumulation EFAD-Tg mice. Neurosci Lett 560:131-6
Gold, Brian T; Zhu, Zude; Brown, Christopher A et al. (2014) White matter integrity is associated with cerebrospinal fluid markers of Alzheimer's disease in normal adults. Neurobiol Aging 35:2263-71
Kanekiyo, Takahisa; Xu, Huaxi; Bu, Guojun (2014) ApoE and A? in Alzheimer's disease: accidental encounters or partners? Neuron 81:740-54
Rodriguez, Gustavo A; Tai, Leon M; LaDu, Mary Jo et al. (2014) Human APOE4 increases microglia reactivity at A? plaques in a mouse model of A? deposition. J Neuroinflammation 11:111
Nwabuisi-Heath, Evelyn; Rebeck, G William; Ladu, Mary Jo et al. (2014) ApoE4 delays dendritic spine formation during neuron development and accelerates loss of mature spines inýývitro. ASN Neuro 6:e00134

Showing the most recent 10 out of 42 publications