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Alzheimer's Disease Research
Completed Award

Photo Pending

Jungsu Kim, Ph.D.

Washington University
St. Louis, MO

Title: New Method to Assess apoE and Abeta Metabolism
Non-Technical Title: Understanding the role of the APOE4 allele in AD

Mentor:
David Holtzman, M.D.
Washington University

Duration: April 1, 2007 - March 31, 2009
Award Type: Research Fellowship
Award Amount: $100,000

Summary:

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 isofom genotype influences risk for AD.

Details:

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 isofom genotype influences risk for AD.

Publications:

Wahrle, S.E., Jiang H., Parsadanian, M., Kim J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C.L., Bales, K.R., Paul, S.M., Holtzman, D.M. (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest. 118(2):671-682. PubMed Icon Google Scholar Icon

Kim J, Castellano JM, Jiang H, Basak JM, Parsadanian M, Pham V, Mason SM, Paul SM, Holtzman DM. Overexpression of low-density lipoprotein receptor in the brain markedly inhibits amyloid deposition and increases extracellular A beta clearance. Neuron. 2009 Dec 10;64(5):632-44. PubMed Icon Google Scholar Icon

Castellano JM, Kim J, Stewart FR, Jiang H, Demattos RB, Patterson BW, Fagan AM, Morris JC, Mawuenyega KG, Cruchaga C, Goate AM, Bales KR, Paul SM, Bateman RJ, Holtzman DM. Human apoE Isoforms Differentially Regulate Brain Amyloid-{beta} Peptide Clearance. Sci Transl Med. 2011 Jun 29;3(89):89ra57. PubMed Icon Google Scholar Icon

Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer's disease. Neuron. 2009 Aug 13;63(3):287-303. Review. PubMed Icon Google Scholar Icon

Kim J, Jiang H, Park S, Eltorai AE, Stewart FR, Yoon H, Basak JM, Finn MB, Holtzman DM. Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. J Neurosci. 2011 Dec 7;31(49):18007-12. PubMed Icon Google Scholar Icon