In Vivo and In Vitro Effects of an Apolipoprotein E Mimetic Peptide on Amyloid-β Pathology

Abstract

Background Apolipoprotein E (ApoE) is the major apolipoprotein present in the high-density lipoprotein-like particles in the central nervous system (CNS). ApoE is involved in various protective functions in CNS including cholesterol transport, anti-inflammatory, and antioxidant effects. An ApoE peptide would be expected to exert protective effects on neuroinflammation. Objective To determine the effects of an ApoE mimetic peptide Ac-hE18A-NH2 on amyloid-β pathology. Method Using human APP/PS1ΔE9 transgenic mice and in vitro studies, we have evaluated the effect of an ApoE mimetic peptide, Ac-hE18A-NH2, on amyloid plaque deposition and inflammation. Results Administration of Ac-hE18A-NH2 to APP/PS1ΔE9 mice for 6 weeks (50 μg/mouse, 3 times a week) significantly improved cognition with a concomitant decrease in amyloid plaque deposition and reduced activated microglia and astrocytes, and increased brain ApoE levels. Oligomeric Aβ42 (oAβ42) and oxidized PAPC (ox-PAPC) inhibited secretion of ApoE in U251 cells, a human astrocyte cell line, and this effect was ameliorated in the presence of peptide Ac-hE18A-NH2. The peptide also increased Aβ42 uptake in a cell line of human macrophages. Conclusions Peptide Ac-hE18A-NH2 attenuates the effects of oxidative stress on ApoE secretion, inhibits amyloid plaque deposition, and thus could be beneficial in the treatment of Alzheimer’s disease.

Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

“…These results suggest that the apoE mimetic peptide Ac-hE18A-NH 2 , analogous to apoE, exerts cytoprotective effects that are independent of effects on plasma cholesterol (138)(139)(140). In support of this, a recent study shows that administration of Ac-hE18A-NH 2 in APP/PS1 ⌬ E9 transgenic mice, a murine model of Alzheimer's disease, inhibits amyloid plaque deposition and improves cognitive function ( 137 ).…”

“…While Ac-hE18A-NH 2 is rapidly cleared from the circulation after IV administration, it continues to exert signifi cant benefi cial effects on aortic lesions for up to a month after suspending peptide administration in mouse models of atherosclerosis ( 135 ). Subsequent studies revealed that Ac-hE18A-NH 2 induces the release of PON-1 and lipid-poor pre ␤ -HDL particles from hepatocytes and also promotes apoE secretion from hepatocytes and macrophages ( 131,133,136,137 ). These studies further showed that Ac-hE18A-NH 2 is recycled by cells, thus enabling the potentiation and prolongation of its anti-atherogenic and anti-infl ammatory effects ( 131 ).…”

Apolipoprotein E as a Therapeutic Target in Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

“…Treatment with synthetic apoE mimetic peptides composed of 12 to 17 amino acids (COG112 and COG1410) which contain the receptor-binding region in apoE but not lipid- or Aβ-binding region, significantly reduced neuroinflammation, tau hyper-phosphorylation and defects in adult neurogenesis in AD mouse models [142, 143]. Additionally, another apoE mimetic peptide consisting of tandem repeats of the apoE receptor-binding region (Ac-hE18A-NH 2 ) reduced Aβ production in wild-type mice [144] and improved cognition with concomitant suppression of glial activation/Aβ deposition in amyloid model mice [145]. However, the effects of these peptides on amyloid pathologies in the presence of human apoE isoforms particularly in apoE4 have not been fully evaluated.…”

High-density lipoprotein mimetics: promises and challenges

“…D-4F in combination with statin reduced severity of arthritis in animal model [15]. The same combination of D-F4 and statin, as well as apoE mimetic peptide Ac-hE18A-NH2, reduced amyloid deposition and improved cognitive function in animal models of Alzheimer’s disease [9, 10]. L-4F reduced insulin resistance and inflammation in animal models of obesity [8].…”

“…ApoA-I mimetics have also been used to reduce obesity and diabetes [8]. ApoA-I and apoE mimetic peptides were shown to reduce amyloid burden in animal and cellular models of Alzheimer’s disease [9, 10]. In context of infectious diseases, apoA-I mimetic peptides reduced inflammation caused by an infection [11] and provided considerable multiple organ protection in sepsis [12].…”