In vivo human apolipoprotein E isoform fractional turnover rates in the CNS.
Apolipoprotein E (ApoE) is the strongest genetic risk factor for Alzheimer's disease and has been implicated in the risk for other neurological disorders. The three common ApoE isoforms (ApoE2, E3, and E4) each differ by a single amino acid, with ApoE4 increasing and ApoE2 decreasing the risk of Alzheimer's disease (AD). Both the isoform and amount of ApoE in the brain modulate AD pathology by altering the extent of amyloid beta (Aβ) peptide deposition. Therefore, quantifying ApoE isoform production and clearance rates may advance our understanding of the role of ApoE in health and disease. To measure the kinetics of ApoE in the central nervous system (CNS), we applied in vivo stable isotope labeling to quantify the fractional turnover rates of ApoE isoforms in 18 cognitively-normal adults and in ApoE3 and ApoE4 targeted-replacement mice. No isoform-specific differences in CNS ApoE3 and ApoE4 turnover rates were observed when measured in human CSF or mouse brain. However, CNS and peripheral ApoE isoform turnover rates differed substantially, which is consistent with previous reports and suggests that the pathways responsible for ApoE metabolism are different in the CNS and the periphery. We also demonstrate a slower turnover rate for CSF ApoE than that for amyloid beta, another molecule critically important in AD pathogenesis.
Department of Neurology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
Kristin R
KR
Wildsmith
Jacob M
JM
Basak
Bruce W
BW
Patterson
Yuriy
Y
Pyatkivskyy
Jungsu
J
Kim
Kevin E
KE
Yarasheski
Jennifer X
JX
Wang
Kwasi G
KG
Mawuenyega
Hong
H
Jiang
Maia
M
Parsadanian
Hyejin
H
Yoon
Tom
T
Kasten
Wendy C
WC
Sigurdson
Chengjie
C
Xiong
Alison
A
Goate
David M
DM
Holtzman
Randall J
RJ
Bateman
D000328:Adult; D016229:Amyloid beta-Peptides; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002247:Carbon Isotopes; D002490:Central Nervous System / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008875:Middle Aged; D020033:Protein Isoforms / Q000097:blood / Q000378:metabolism; D055815:Young Adult
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D002247:Carbon Isotopes; D020033:Protein Isoforms