Genetic studies indicate that the E4 allele of apolipoprotein E (apoE) is a major risk factor for Alzheimer's disease (AD) while the presence of the E2 allele may be neuroprotective. ApoE is expressed by glial cells in the central nervous system (CNS) and at even higher levels in the setting of injury. Through little is known about the biological role of apoE in the CNS, data indicate the apoE-containing lipoproteins can alter neurite morphology of neurons derived from both the peripheral nervous system as well as the CNS. Human apoE3 can increase neurite extension whereas apoE4 has little effect or decreases extension. Importantly, the effects of apoE, can increase neurite extension whereas apoE4 has either little effect. The examined to date are mediated through the low density lipoprotein receptor-related protein (LRP). LRP is a large, multifunctional cell surface receptor which is expressed by CNS neurons and mediates endocytosis of several ligands including apoE-containing lipoproteins. Preliminary data also suggest an important role for LRP to axonal outgrowth in vivo. It is hypothesized that LRP mediates the biological effects of apoE on CNS neurons. Thus understanding the normal role of LRP in the CNS as well as the mechanism of isoform-specific differences in apoE=LRP effects may provide insight into AD pathogenesis. In this proposal, the applicants will pursue (1) the biological functions of LRP, (2) the importance of apoE-LRP interactions in vitro and in vivo, and (3) the cell biological processes mediating isoform-specific effects of apoE on CNS neurons.
The specific aims are as follows: 1. To determine whether apoE isoforms differentially influence neurite outgrowth and cell survival in primary culture of CNS neurons through LRP. 2. To determine the effects of primary culture of CNS neurons through LRP inhibitor and anti-LRP antibodies on developing CNS neurites in vitro and in vivo. 3. To examine the expression of apoE, LRP, and other molecules potentially relaxant to the effects of apoE (LDL, receptor and VLDL receptor) in mature rat brain. 4. To determine the molecular mechanism (s) by which apoE/LRP responsible for their interactions. These studies should provide nw insights into the normal function of apoE and LRP in the CNS and pathogenesis of AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013956-02
Application #
2517057
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1996-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Han, Byung Hee; Zhou, Meng-Liang; Johnson, Andrew W et al. (2015) Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice. Proc Natl Acad Sci U S A 112:E881-90
Kim, Jaekwang; Yoon, Hyejin; Horie, Takahiro et al. (2015) microRNA-33 Regulates ApoE Lipidation and Amyloid-? Metabolism in the Brain. J Neurosci 35:14717-26
Shin, Soomin; Walz, Katharine A; Archambault, Angela S et al. (2014) Apolipoprotein E mediation of neuro-inflammation in a murine model of multiple sclerosis. J Neuroimmunol 271:8-17
Dikranian, Krikor; Holtzman, David M (2014) The Ultrastructural Identity of Alzheimer's Pathology: Lessons from Animal Models. J Neurol Disord 2:e111
Verghese, Philip B; Castellano, Joseph M; Garai, Kanchan et al. (2013) ApoE influences amyloid-? (A?) clearance despite minimal apoE/A? association in physiological conditions. Proc Natl Acad Sci U S A 110:E1807-16
Esparza, Thomas J; Zhao, Hanzhi; Cirrito, John R et al. (2013) Amyloid-? oligomerization in Alzheimer dementia versus high-pathology controls. Ann Neurol 73:104-19
Dikranian, Krikor; Kim, Jungsu; Stewart, Floy R et al. (2012) Ultrastructural studies in APP/PS1 mice expressing human ApoE isoforms: implications for Alzheimer's disease. Int J Clin Exp Pathol 5:482-95
Basak, Jacob M; Kim, Jungsu; Pyatkivskyy, Yuriy et al. (2012) Measurement of apolipoprotein E and amyloid ? clearance rates in the mouse brain using bolus stable isotope labeling. Mol Neurodegener 7:14
Basak, Jacob M; Verghese, Philip B; Yoon, Hyejin et al. (2012) Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of A? uptake and degradation by astrocytes. J Biol Chem 287:13959-71
Wildsmith, Kristin R; Basak, Jacob M; Patterson, Bruce W et al. (2012) In vivo human apolipoprotein E isoform fractional turnover rates in the CNS. PLoS One 7:e38013

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