Recent evidence indicates that inflammation may significantly contribute to the pathogenesis of Alzheimer’s disease (AD). Since the apo A-I mimetic peptide D-4F has been shown to inhibit atherosclerotic lesion formation and regress already existing lesions (in the presence of pravastatin) and the peptide also decreases brain arteriole inflammation, we undertook a study to evaluate the efficacy of oral D-4F co-administered with pravastatin on cognitive function and amyloid β (Aβ) burden in the hippocampus of APPSwe-PS1ΔE9 mice. Three groups of male mice were administered D-4F and pravastatin, Scrambled D-4F (ScD-4F, a control peptide) and pravastatin in drinking water, while drinking water alone served as control. The escape latency in the Morris Water Maze test was significantly shorter for the D-4F+statin administered animals compared to the other two groups. While the hippocampal region of the brain was covered with 4.2±0.5 and 3.8±0.6% of Aβ load in the control and ScD-4F+statin administered groups, in the D-4F+statin administered group Aβ load was only 1.6±0.1%. Furthermore, there was a significant decrease in the number of activated microglia (p<0.05 vs the other two groups) and activated astrocytes (p<0.05 vs control) upon oral D-4F+statin treatment. Inflammatory markers TNFα and IL-1β levels were decreased significantly in the D-4F+statin group compared to the other two groups (for IL-1β p<0.01 vs the other two groups and for TNF-α p<0.001 vs control) and the expression of MCP-1 were also less in D-4F+statin administered group compared to the other two groups. These results suggest that the apo A-I mimetic peptide inhibits amyloid β deposition and improves cognitive function via exerting anti-inflammatory properties in the brain.
Objective The apolipoprotein E mimetic peptide Ac-hE18A-NH2, capable of reducing plasma cholesterol and possessing anti-inflammatory properties, was compared with the well-studied anti-atherogenic apoA-I mimetic peptide 4F for reducing lesion formation in female apoE null mice with already existing lesions. Methods and Results In initial experiments, Ac-hE18A-NH2 was administered retro-orbitally two or three times weekly for 6 to 8 weeks, while peptide 4F was administered intraperitoneally every day for the same period. Age matched controls were injected with saline every day. At the end of the treatment period, plasma cholesterol levels of Ac-hE18A-NH2 administered mice were significantly lower than in 4F and control mice. However, both 4F and Ac-hE18A-NH2 showed reduced lesion areas in en face lesion analysis to a similar extent compared to the control group, while paraoxonase-1 (PON-1) activity was increased only in the Ac-hE18A-NH2 group. In the third experiment, both peptides were administered at the same dose, frequency, and route of administration. The reduction in en face lesions with Ac-hE18A-NH2 was significantly greater than the 4F and control groups, although lesions in 4F-treated mice were also significantly reduced compared with controls. Both peptide groups had significantly reduced plasma lipid hydroperoxides, but only the Ac-hE18A-NH2 group had significantly reduced serum amyloid A levels. HDL and plasma inflammatory indices were significantly reduced in both peptide groups compared with controls. Conclusions Although both peptides had similar anti-inflammatory properties, Ac-hE18A-NH2 was more effective in inhibiting lesions than 4F at the same dose, frequency, and route of administration, perhaps due to its cholesterol reducing properties.
Objective We investigated two apoE mimetic peptides with similar long-term plasma cholesterol reducing abilities for their effects on atherosclerotic lesions in Western diet-fed female LDL receptor (LDL-R) null mice. Methods and Results Single doses of peptides Ac-hE18A-NH2 and mR18L were administered retro-orbitally to LDL-R null mice on Western diet and plasma cholesterol was measured at 10 min, 4 hours, and 24 hours post administration. Peptide mR18L and not Ac-hE18A-NH2 reduced plasma cholesterol levels significantly at 4 hours post administration. However, multiple administrations (100 μg/mouse twice weekly for 8 weeks) resulted in a similar reduction in plasma cholesterol. Only the plasma from the Ac-hE18A-NH2 group had significantly reduced reactive oxygen species levels at the end of the treatment protocol. Both mR18L and Ac-hE18A-NH2 showed reduced atherosclerotic lesion areas. However, peptide Ac-hE18A-NH2 was significantly more effective in inhibiting atherosclerosis. Both peptides reduced total plaque macrophage load compared to the saline treated animals, with peptide Ac-hE18A-NH2 having a greater reduction. Incubation of HepG2 cells and THP-1 monocyte-derived macrophages with both peptides in the presence of oxidized phospholipid showed that Ac-hE18A-NH2 promotes the secretion of apoE from the cells whereas mR18L does not. Conclusions Despite similar reductions in plasma cholesterol levels, Ac-hE18A-NH2 was more effective in inhibiting lesions than mR18L, possibly due to its ability to promote the secretion of apoE from hepatocytes and macrophages.
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.
Objective We recently described anti-atherogenic properties of the dual domain peptide Ac-hE18A-NH2 derived by covalently linking the heparin binding domain 141-150 of apoE to 18A, a class A amphipathic helical peptide. In this paper we have compared the properties of Ac-hE18A-NH2 with the non-heparin binding 151-160 region of apoE linked to 18A (Ac-nhE18A-NH2). Methods and Results Both peptides were highly helical in solution and in association with lipids. Ac-hE18A-NH2 and not Ac-nhE18A-NH2 enhanced uptake of low density lipoprotein (LDL) in HepG2 cells. While Ac-hE18A-NH2 retarded the electrophoretic mobility of LDL, Ac-nhE18A-NH2 slightly enhanced mobility. Ac-hE18A-NH2 reduced monocyte association with endothelial cells, while Ac-nhE18A-NH2 increased it. Ac-hE18A-NH2 also reduced lipid hydroperoxide content of LDL while Ac-nhE18A-NH2 increased it. A single administration of Ac-hE18A-NH2 (100 μg/mouse) into apoE null mice dramatically reduced cholesterol (from 600 mg/dL to 180 mg/dL at five min. and to 60 mg/dL at five h) while Ac-nhE18A-NH2 had no effect. Administration (100μg/mouse/day, three days a week) into apoE null mice for six weeks showed Ac-hE18A-NH2 group having a moderate aortic sinus lesion reduction compared with the control group (−15.1%), while the Ac-nhE18A-NH2 administered group had increased lesion area (+33.0% vs controls and 36.1% vs Ac-hE18A-NH2). Plasma from mice administered Ac-hE18A-NH2 for six weeks showed a significant reduction in plasma cholesterol and triglyceride levels and increase in paraoxonase-1 (PON-1) activity compared to controls, while Ac-nhE18A-NH2 caused no change in plasma cholesterol and decreased PON-1 activity. Conclusion It is proposed that Ac-hE18A-NH2 reduced lesion progression in apoE null mice due to its anti-inflammatory and lipoprotein clearing properties, while Ac-nhE18A-NH2 exhibited pro-atherogenic effects.
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