ApoE4 is the major identified genetic risk factor for AD, present in more than 40% of the cases. ApoE risk is markedly modulated by prior head injury and possibly, estrogen and NSAID use, important environmental factors, modulating risk. ApoE4 risk is associated with increased amyloid deposits, primarily abeta1-40. Beta-amyloid plaque formation in human amyloid precursor (APP) transgenic mice is dramatically reduced in an ApoE knockout background which implies a major regulatory role for ApoE levels in beta-amyloid peptide (Abeta) metabolism. This proposal seeks to address gaps in our knowledge about how ApoE isoforms and levels regulate Abeta deposition and whether other factors believed to modulate AD risk could do so by modulating ApoE levels. In order to study native ApoE lipoprotein effects with appropriate regulation of expression, we are employing human ApoE3 and E4 transgenics driven by their own promoter and enhancer elements. We first address isoform effects on deposit formation, mechanism of action and relationship to ApoE levels and regulation using an organotypic hippocampal slice culture system in which we have shown that TGFbeta, an injury induced cytokine, and ApoE can regulate Abeta deposition. We then proceed to study the role of ApoE isoform levels on amyloid plaque formation and synaptic alterations in brains of APP transgenic mice and AD patients. These experiments will provide new information on the role of ApoE isoforms in plaque pathogenesis and how AD risk factors or therapeutics may regulate Abeta accumulation by manipulating ApoE levels. Since ApoE risk regulates AD onset, this proposal should contribute to efforts to delay AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Specialized Center (P50)
Project #
3P50AG016570-02S1
Application #
6315230
Study Section
Project Start
2000-06-01
Project End
2001-03-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
2
Fiscal Year
2000
Total Cost
$456,808
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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