Although abundant new information has recently been collected on the genetic and environmental risk factors associated with Alzheimer's disease, there is still no consensus on the critical pathway leading to neuropathology. The """"""""amyloid hypothesis"""""""", which dominates much current research effort, has both strengths and weaknesses. One aspect of the postulated role for amyloid that is particularly contentious is the extent to which it is a direct cause of neuronal degeneration, as opposed to participating in a cascade of events that ultimately leads to neuronal dysfunction and death. Other genetic risk factors for proteins involved in AD include apolipoprotein E (apoE) and there is accumulating evidence that apoE4 may directly contribute to AD neuropathology. In particular, apoE4 has been shown to exhibit neurotoxic effects in vitro. This toxicity may be associated with proteolytic generation of a shortened form of apoE (truncated apoE), which is more abundant in AD brain tissue. In addition, several lines of evidence suggest that a C-terminal fragment of apoE binds to, and co-localizes with, amyloid. The work proposed here will examine the hypothesis that proteolytic fragments of apoE contribute to both neuropathology and amyloid deposition. A combination of immunohistochemical, biochemical, and tissue culture studies will be used to: examine the extent of apoE proteolysis in human brain and apoE transgenic mouse brain; identify the cellular source of apoE and its proteolysis in the CNS; study the role of specific receptors in apoE neurotoxicity; study the effect of C-terminal apoE on ABeta aggregation and activity; and localize apoE fragments at sites of AD pathology. The goal is to pursue evidence in support or against the major hypothesis that proteolysis of apoE contributes to AD pathology.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020249-05
Application #
7118113
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Snyder, Stephen D
Project Start
2002-09-30
Project End
2009-02-17
Budget Start
2006-09-01
Budget End
2009-02-17
Support Year
5
Fiscal Year
2006
Total Cost
$402,166
Indirect Cost
Name
University of Cincinnati
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
Crutcher, K A; Lilley, H N; Anthony, S R et al. (2010) Full-length apolipoprotein E protects against the neurotoxicity of an apoE-related peptide. Brain Res 1306:106-15
Shelton, Shirley B; Pettigrew, David B; Hermann, Alison D et al. (2008) A simple, efficient tool for assessment of mice after unilateral cortex injury. J Neurosci Methods 168:431-42
Zhou, Weidong; Xu, Di; Peng, Xiaoxia et al. (2008) Meta-analysis of APOE4 allele and outcome after traumatic brain injury. J Neurotrauma 25:279-90
Dobson, Curtis B; Sales, Sean D; Hoggard, Patrick et al. (2006) The receptor-binding region of human apolipoprotein E has direct anti-infective activity. J Infect Dis 193:442-50
Zhou, W; Scott, S A; Shelton, S B et al. (2006) Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimer's disease. Neuroscience 143:689-701
White, Jill A; Manelli, Arlene M; Holmberg, Kristina H et al. (2005) Differential effects of oligomeric and fibrillar amyloid-beta 1-42 on astrocyte-mediated inflammation. Neurobiol Dis 18:459-65
Crutcher, Keith A (2004) Apolipoprotein E is a prime suspect, not just an accomplice, in Alzheimer's disease. J Mol Neurosci 23:181-8