Role of a Lipid-Regulating Protein in Alzheimer's Disease Pathogenesis

Jungsu Kim, PhD
Washington University (St. Louis, MO)
Year Awarded:
2012
Grant Duration:
July 1, 2012 to June 30, 2014
Disease:
Alzheimer's
Award Amount:
$150,000
Grant Reference ID:
A2012421
Award Type:
Pilot
Award Region:
US Midwestern

Role of a LDLR-interacting protein in LDLR, ApoE, and Abeta Metabolism

Summary

Genetic variants of the Apolipoprotein E (ApoE) gene represent the strongest genetic risk factor for Alzheimer's disease (AD). Dr. Jungsu Kim's previous studies suggest that low density lipoprotein receptor (LDLR) binds to ApoE protein and dramatically affects the development of AD. In the current experiments, he is investigating the role of a novel LDLR-interacting protein in regulating LDLR and ApoE protein levels in order to test its potential as an AD therapeutic.

Details

Dr. Jungsu Kim and his team are investigating the role of a lipid-regulating protein in Alzheimer's disease pathogenesis. A variant of the Apolipoprotein E (ApoE) gene represents the strongest genetic risk factor for Alzheimer's disease. ApoE protein binds to lipids and regulates the amount of lipids in the brain. Kim's previous studies suggest that low density lipoprotein receptor (LDLR) protein decreases ApoE protein levels and dramatically decreases toxic amyloid deposition in the brain. Therefore, increasing LDLR protein levels in the brain may represent a novel Alzheimer's disease treatment strategy. Interestingly, increase of LDLR levels is also being pursed to treat atherosclerosis and several other common heart diseases. Kim is studying the role of a novel LDLR-interacting protein in regulating LDLR and ApoE protein levels in the brain, in order to test its potential as an Alzheimer's disease therapeutic. To test the hypothesis, he is using two novel methods that he and his collaborators have developed over the last few years. One of the methods will efficiently determine whether a novel LDLR-interacting protein affects amyloid deposition in the brain by using a gene therapy approach. The other method utilizes a new instrument that allows accurate measurement of the weight of small protein fragments that are being experimentally tagged with “heavy” atoms. If an increase of this novel LDLR-interacting protein level significantly inhibits toxic amyloid formation and prevents Alzheimer's disease symptoms in animal models, the scientists plan to screen thousands of existing chemicals to identify compounds that might be tested as potential new drug candidates.

Publications

Basak JM*, Kim J*, Pyatkivskyy Y, Wildsmith KR, Jiang H, Parsadanian M, Patterson BW, Bateman RJ, Holtzman DM (2012b) Measurement of apolipoprotein E and amyloid beta clearance rates in the mouse brain using bolus stable isotope labeling. Mol Neurodegener 7:14. PubMed Icon Google Scholar Icon