New Method to Assess ApoE and Abeta Metabolism

About the Research Project
Program
Award Type
Postdoctoral Fellowship
Award Amount
$100,000
Active Dates
April 01, 2007 - March 31, 2009
Grant ID
A2007620
Mentor(s)
David Holtzman, Washington University in St.Louis
Goals
The hypothesis being tested is that different human apoE isoforms and lipidation states of apoE alters apoE and Abeta clearance in the CNS. We further hypothesize that the perturbation in regulation of apoE metabolism will then influence Abeta metabolism and will alter both the time course and amount of Abeta depostion in brain. Results from these experiments may provide insights into normal apoE metabolism in the CNS as well as clarify why APOE isoform genotype influences risk for AD.
Summary
Alzheimer’s disease (AD) is the most common cause of dementia. Mutations in specific genes (APP, PSEN1, and PSEN2) cause rare forms of familial AD. While these mutations have been very useful, >99% of AD (late-onset) does not appear to be due to these mutations. Defects in clearance of Abeta from brain could underline many cases of sporadic AD. There is only one proven genetic risk factor for both early and late-onset AD, one’s APOE genotype. ApoE4 is associated with an increased risk and apoE2 is associated with a decreased risk for AD. A large amount of evidence suggests that apoE is likely to influence risk for AD by acting as a molecular chaperone for Abeta and influencing Abeta fibrillogenesis and clearance. The hypothesis being tested is that different human apoE isoforms and lipidation states of apoE alters apoE and Abeta clearance in the CNS. We further hypothesize that the perturbation in regulation of apoE metabolism will then influence Abeta metabolism and will alter both the time course and amount of Abeta depostion in brain. Results from these experiments may provide insights into normal apoE metabolism in the CNS as well as clarify why APOE isoform genotype influences risk for AD.
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