Metabolism of the protein (ApoE) that increases risk of Alzheimer's Disease in humans.

Randall Bateman, MD
Washington University (St. Louis, MO)
Year Awarded:
2008
Grant Duration:
April 1, 2008 to March 31, 2010
Disease:
Alzheimer's
Award Amount:
$150,000
Grant Reference ID:
A2008345
Award Type:
Pilot
Award Region:
US Midwestern

Human CNS-Apolipoprotein E Isoform Production and Clearance

Summary

Although ApoE is the strongest genetic risk factor for Alzheimer's disease, relatively little is known about the how ApoE contributes to that risk. This study seeks to characterize basic biological differences between three different ApoE alleles.

Details


Alzheimer's disease is the most common cause of dementia, and the most feared disease of Americans over the age of 65. ApoE is the strongest genetic risk factor for Alzheimer's disease, and is a potential target for disease-modifying therapies. The ApoE4 allele, which occurs in 15 percent of the population, increases one's risk of developing Alzheimer's Disease by 3-fold, while two copies of ApoE4 increase this risk by 12-fold. Whereas the E2 allele, occurring in 7 percent of the population, decreases one's risk of developing Alzeimer's disease. The hypothesis being tested is the three ApoE isoforms (E2, E3 and E4) have different rates of synthesis and clearance. We will measure the metabolism of ApoE from the cerebrospinal fluid of young, non-demented participants. This study will provide an important link regarding how ApoE4 may be involved in the pathophysiology of Alzheimer's disease, and may lead to improved therapeutics, which target the major genetic risk factor of Alzheimer's disease, ApoE.

Publications

Wildsmith KR, Han B, Bateman RJ. Method for the simultaneous quantitation of apolipoprotein E isoforms using tandem mass spectrometry. Anal Biochem. 2009 Dec 1;395(1):116-8. Epub 2009 Aug 3.  

Wildsmith KR, Han B, Bateman RJ. (2009) Method for the simultaneous quantitation of apolipoprotein E isoforms using tandem mass spectrometry. Anal Biochem. 2009 395(1),116-118  

Wildsmith, K.R., Patterson, B.W., Bateman, R.J. 2010.Using Tandem MS to Elucidate the Metabolism of CNS-derived Apolipoprotein E3 and Apolipoprotein E4 in Young Normal Control Participants. J Am Soc Mass Spectrom 21(5S):ThP140 [PMID:nd][link not available]

Wildsmith, K.R., Sigurdson, W.C., Bateman, R.J. 2009. Using Stable Isotopes and Tandem MS to study the Metabolism of CNS-derived Apolipoprotein E Isoforms. J Am Soc Mass Spectrom 20(5S):MP601 [PMID:nd][link not available]

Wildsmith, K.R., Browning, K.R., Mawuenyega, K.G., Davis, A.E., Townsend, R.R., and Bateman, R.J. (2008) Quantitating CNS-derived Apolipoprotein E Isoforms using Bottom-up Proteomics. J Am Soc [PMID:nd][link not available]