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.

Atherogenesis inhibition induced by magnesium-chloride fortification of drinking water.

Magnesium (Mg) modulates blood lipid levels, atherogenesis, and atherosclerosis in rabbits, when supplemented to diet. We have recently reported that a high concentration (50 g/L) of Mg sulfate fortification of drinking water attenuates atherogenesis in male and female LDL-receptor-deficient mice fed a high-cholesterol diet. The aims of the current study were to examine whether lower concentrations and another Mg salt could also have such an antiatherogenic effect. Thirty male LDL-receptor-deficient mice were divided into three groups (n=10 in each group). The mice received either distilled water or water fortified with 0.83 g or with 8.3 g Mg-chloride per liter. In the first (27 wk) and second (5 wk) stages of the experiment, the mice received normal chow and Western-type diet, respectively. Blood was drawn for determination of plasma Mg, calcium, and lipid levels. The extent of atherosclerotic lesions was determined at the aortic sinus. Magnesium-chloride fortification of drinking water did not result in higher plasma Mg concentrations, whereas a trend toward lower plasma calcium concentrations did not reach statistical significance. Even though plasma lipid levels were similar at the beginning and the end of the study, there were decreased plasma cholesterol and triglyceride levels in the Mg groups after stage I. The atherosclerosis extent at the aortic sinus was significantly decreased in the 8.3-g Mg-chloride/L group (23,437 +/- 10,083 micron2) compared with the control group (65,937 +/- 31,761 microm2). There was also a trend toward lower atherosclerosis extent at the aortic sinus in the 0.83-g Mg-chloride/L group. An additional Mg salt (Mg-chloride) fortification of drinking water is capable of inhibiting atherogenesis in male LDL-receptor-deficient mice. That is done in a lower concentration of Mg than previously reported.

The antiatherogenic effect of allicin: possible mode of action.

OBJECTIVE: Garlic (Allium sativum) has been suggested to affect several cardiovascular risk factors. Its antiatherosclerotic properties are mainly attributed to allicin that is produced upon crushing of the garlic clove. Most previous studies used various garlic preparations in which allicin levels were not well defined. In the present study, we evaluated the effects of pure allicin on atherogenesis in experimental mouse models. METHODS AND RESULTS: Daily dietary supplement of allicin, 9 mg/kg body weight, reduced the atherosclerotic plaque area by 68.9 and 56.8% in apolipoprotein E-deficient and low-density lipoprotein (LDL) receptor knockout mice, respectively, as compared with control mice. LDL isolated from allicin-treated groups was more resistant to CuSO(4)-induced oxidation ex vivo than LDL isolated from control mice. Incubation of mouse plasma with (3)H-labeled allicin showed binding of allicin to lipoproteins. By using electron spin resonance, we demonstrated reduced Cu(2+) binding to LDL following allicin treatment. LDL treatment with allicin significantly inhibited both native LDL and oxidized LDL degradation by isolated mouse macrophages. CONCLUSIONS: By using a pure allicin preparation, we were able to show that allicin may affect atherosclerosis not only by acting as an antioxidant, but also by other mechanisms, such as lipoprotein modification and inhibition of LDL uptake and degradation by macrophages.