Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins.
Apolipoprotein E4 (apoE4), the leading genetic risk factor for Alzheimer's disease (AD), is less lipidated compared to the most common and AD-benign allele, apoE3. We have recently shown that i.p. injections of the ATP-binding cassette A1 (ABCA1) agonist peptide CS-6253 to apoE mice reverse the hypolipidation of apoE4 and the associated brain pathology and behavioral deficits. While in the brain apoE is the main cholesterol transporter, in the periphery apoE and apoA-I both serve as the major cholesterol transporters. We presently investigated the extent to which apoE genotype and CS-6253 treatment to apoE3 and apoE4-targeted replacement mice affects the plasma levels and lipid particle distribution of apoE, and those of plasma and brain apoA-I and apoJ. This revealed that plasma levels of apoE4 were lower and eluted faster following FPLC than plasma apoE3. Treatment with CS-6253 increased the levels of plasma apoE4 and rendered the elution profile of apoE4 similar to that of apoE3. Similarly, the levels of plasma apoA-I were lower in the apoE4 mice compared to apoE3 mice, and this effect was partially reversed by CS-6253. Conversely, the levels of apoA-I in the brain which were higher in the apoE4 mice, were unaffected by CS-6253. The plasma levels of apoJ were higher in apoE4 mice than apoE3 mice and this effect was abolished by CS-6253. Similar but less pronounced effects were obtained in the brain. In conclusion, these results suggest that apoE4 affects the levels of apoA-I and apoJ and that the anti-apoE4 beneficial effects of CS-6253 may be related to both central and peripheral mechanisms.
The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.
Anat
A
Boehm-Cagan
The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.
Roni
R
Bar
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel.|The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer 5265601, Israel.
Dror
D
Harats
The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer 5265601, Israel.
Aviv
A
Shaish
The Bert W. Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer 5265601, Israel.
Hana
H
Levkovitz
Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California, 94720, United States of America.
John K
JK
Bielicki
Artery Therapeutics, Inc. San Ramon, California, United States of America.
Jan O
JO
Johansson
The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel.
Daniel M
DM
Michaelson
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D005838:Genotype; D008074:Lipoproteins / Q000097:blood* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D008074:Lipoproteins; D010446:Peptide Fragments; D010455:Peptides; C577833:Abca1 protein, mouse; C000607327:CS-6253