The production of apolipoprotein (apo) E in the brain increases dramatically after injury suggesting a role for apo E in tissue remodeling that is related to its function as a cholesterol transporting protein. In humans, apo E can be found as three isoforms: apo E2, apo E3 and apo E4. The apo E4 isoform is a susceptibility factor for late-onset Alzheimer's disease. Recovery from ischemic stroke is also impaired in patients carrying apo E4. The mechanism by which apo E4 increases the risk for neurodegenerative diseases is currently under investigation. In this proposal we want to test if the ability of apo E to induce neuronal cell apoptosis could influence how the brain recovers from injury that results from ischemic stroke. We will use experimental models that mimic neuronal injury following stroke to evaluate apoptosis induced by the different recombinant human apo E isoforms. We suggest that apo E4 is more potent in inducing neuronal apoptosis than apo E3 or apo E2. We also propose to evaluate the involvement of members of the low-density lipoprotein (LDL) receptor superfamily in this apoptogenic function of apo E. Finally, we will test whether apo J, another apolipoprotein that is upregulated in the brain after stroke-induced injury, modulates apo E- mediated induction of apoptosis. Stroke-associated dementia is a major cause for disability among the elderly population. With the experiments proposed here we will gather evidence about this new function of apo E and how it may play an important role in the exacerbation of neurodegenerative diseases that result from stroke-induced brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32NS041872-03
Application #
6640740
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (02))
Program Officer
Jacobs, Tom P
Project Start
2002-01-01
Project End
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
3
Fiscal Year
2003
Total Cost
$56,308
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zerbinatti, Celina V; Wahrle, Suzanne E; Kim, Hyungjin et al. (2006) Apolipoprotein E and low density lipoprotein receptor-related protein facilitate intraneuronal Abeta42 accumulation in amyloid model mice. J Biol Chem 281:36180-6
Cam, Judy A; Zerbinatti, Celina V; Li, Yonghe et al. (2005) Rapid endocytosis of the low density lipoprotein receptor-related protein modulates cell surface distribution and processing of the beta-amyloid precursor protein. J Biol Chem 280:15464-70
Zerbinatti, Celina V; Bu, Guojun (2005) LRP and Alzheimer's disease. Rev Neurosci 16:123-35
Zerbinatti, Celina V; Wozniak, David F; Cirrito, John et al. (2004) Increased soluble amyloid-beta peptide and memory deficits in amyloid model mice overexpressing the low-density lipoprotein receptor-related protein. Proc Natl Acad Sci U S A 101:1075-80
Cam, Judy A; Zerbinatti, Celina V; Knisely, Jane M et al. (2004) The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production. J Biol Chem 279:29639-46