Abstract
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.
Highlights
Apolipoprotein E is the most abundant lipoprotein in the brain, where it is produced mostly by astrocytes [1]
The total levels of Apolipoprotein E (apoE) in the plasma were lower in the control Apolipoprotein E4 (apoE4) mice compared to the corresponding apoE3 mice (1.00 ± 0.03 versus 0.59 ± 0.06 for control apoE3 and control apoE4 mice, respectively). This effect was virtually abolished by the CS-6253 treatment, which elevated the levels of apoE in the treated-apoE4 mice while having no effect on the corresponding plasma level of the CS-6253-treated apoE3 mice (0.87 ± 0.05 versus 0.80 ± 0.03 for CS-6253-treated apoE3 and CS-6253-treated apoE4, respectively)
Further post hoc analysis revealed that the levels of apoE were significantly lower in the control apoE4 mouse group compared to the control apoE3 mice (p
Summary
Apolipoprotein E (apoE) is the most abundant lipoprotein in the brain, where it is produced mostly by astrocytes [1]. ApoE is synthesized in the periphery, typically by the liver and by macrophages [2], and is an important serum lipoprotein. ApoE exists as three major isoforms, PLOS ONE | DOI:10.1371/journal.pone.0166195. ABCA1 agonist Affects Plasma and Brain Apolipoproteins. Therapeutics, Inc. provided support in the form of salaries for author JOJ, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this authors is articulated in the ‘author contributions’ section
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