Genetic studies have shown that the E4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease (AD). Both in vitro and more recently in vivo data in both humans and mice strongly suggest a major factor underlying this increased risk relates in some way to the ability of apoE to enhance amyloid Beta (ABeta) deposition. The mechanisms underlying this effect of apoE as well as its isoform specific effects remain unclear. In the brain, apoE is primarily synthesized by astrocytes that secrete apoE in high density lipoprotein (HDL)-like particles. Recent data suggest that the properties of apoE-containing lipoproteins produced in the brain may be unique in regard to their potential function and interactions with other proteins. The multi-ligand apoE receptor known as LRP is expressed at high levels by neural cells. Recent genetic studies suggest that certain alleles of another LRP ligand, alpha2M, as well as specific alleles of LRP itself may also act as AD risk factors. This suggests that clearance of LRP ligands may in some way be involved in the pathogenesis of AD. There is now compelling data that apoE is necessary for fibrillar ABeta deposition in vivo. APPV717F +/+ transgenic mice which develop fibrillar ABeta deposition by 6 months of age were found to have no fibrillar Abeta deposits and a marked decreased in ABeta deposition. This suggests that mouse apoE-containing lipoproteins produced in the brain be in some way required for ABeta deposition. Two non-mutually exclusive possibilities seem likely to explain the influence of apoE on ABeta deposition: (1) apoE/ABeta interactions facilitates conversion of soluble ABeta to fibrillar ABeta and (2) apoE/ABeta interactions influence ABeta clearance. The goal of these studies is to study the interaction of astrocyte-secreted apoE isoforms and ABeta and to determine how these interactions influence ABeta deposition. It is hypothesized that the level of astrocyte-secreted apoE/lipoproteins will determine the amount of ABeta deposition in vivo. Sub-hypotheses are that (1) apoE4 will result in greater ABeta deposition through enhancing ABeta fibrillogenesis more than other apoE isoforms and (2)apoE influences the amount of fibrillar ABeta by affecting the clearance of apoE/ABeta complexes via LRP. These hypotheses will be tested in the following specific alms: 1. To determine the amount of Abeta deposition and other AD neuropathology in 2 lines of APP transgenic mice which express human apoE2, E3, E4 or mouse apoE. 2. To characterize astrocyte-secreted apoE/lipoproteins and determine their influence on ABeta fibril formation utilizing several techniques. 3. To examine the nature of the association between astrocyte-secreted apoE/lipoproteins and ABeta and determine whether cellular uptake and degradation of apoE/ABeta complexes is modulated via LRP. 4. To determine whether altering expression of LRP or LRP domains influences ABeta levels and deposition in vivo. These studies with physiological preparations of apoE as well as both in vivo and in vitro models should provide new insights into mechanisms underlying the link between apoE, LRP, ABeta, and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013956-05
Application #
6168842
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Snyder, D Stephen
Project Start
1996-09-01
Project End
2004-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
2000
Total Cost
$275,401
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
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
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
Roh, Jee Hoon; Huang, Yafei; Bero, Adam W et al. (2012) Disruption of the sleep-wake cycle and diurnal fluctuation of ?-amyloid in mice with Alzheimer's disease pathology. Sci Transl Med 4:150ra122
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

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