Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study.

OBJECTIVE: Little is known about the transfer of essential fatty acids (FAs) across the human blood-brain barrier (BBB) in adulthood. In this study, we investigated whether oral supplementation with omega-3 (n-3) FAs would change the FA profile of the cerebrospinal fluid (CSF). METHODS: A total of 33 patients (18 receiving the n-3 FA supplement and 15 receiving placebo) were included in the study. These patients were participants in the double-blind, placebo-controlled randomized OmegAD study in which 204 patients with mild Alzheimer's disease (AD) received 2.3 g n-3 FA [high in docosahexaenoic acid (DHA)] or placebo daily for 6 months. CSF FA levels were related to changes in plasma FA and to CSF biomarkers of AD and inflammation. RESULTS: At 6 months, the n-3 FA supplement group displayed significant increases in CSF (and plasma) eicosapentaenoic acid (EPA), DHA and total n-3 FA levels (P < 0.01), whereas no changes were observed in the placebo group. Changes in CSF and plasma levels of EPA and n-3 docosapentaenoic acid were strongly correlated, in contrast to those of DHA. Changes in DHA levels in CSF were inversely correlated with CSF levels of total and phosphorylated tau, and directly correlated with soluble interleukin-1 receptor type II. Thus, the more DHA increased in CSF, the greater the change in CSF AD/inflammatory biomarkers. CONCLUSIONS: Oral supplementation with n-3 FAs conferred changes in the n-3 FA profile in CSF, suggesting transfer of these FAs across the BBB in adults.

Studies on brain volume, Alzheimer-related proteins and cytokines in mice with chronic overexpression of IL-1 receptor antagonist.

Inflammation is associated with both acute and chronic neurological disorders, including stroke and Alzheimer's disease (AD). Cytokines such as interleukin (IL)-1 have several activities in the brain both under physiological and pathophysiological conditions. The objective of this study was to evaluate consequences of the central blockade of IL-1 transmission in a previously developed transgenic mouse strain with brain-directed overexpression of human soluble IL-1 receptor antagonist (Tg hsIL-1ra). Effects on brain morphology and brain levels of the AD-related proteins beta-amyloid precursor protein (APP) and presenilin 1(PS1), as well as the levels of IL-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) were analysed in homozygotic and heterozygotic mice and wild type (WT) controls, of both genders and of young (30-40 days) and adult (13-14 months) age. A marked reduction in brain volume was observed in transgenic mice as determined by volumetry. Western blot analysis showed higher levels of APP, but lower levels of PS1, in adult animals than in young ones. In the cerebellum, heterozygotic (Tg hsIL-1ra(+/-)) mice had lower levels of APP and PS1 than WT mice. With one exception, there were no genotypic differences in the levels of IL-1beta, IL-6 and TNF-alpha. The cytokine levels were generally higher in adult than in young mice. In conclusion, the chronic blockade of IL-1 signalling in the brain was associated with an atrophic phenotype of the brain, and with modified levels of APP and PS1. Brain-directed overexpression of hsIL-1ra was not followed by major compensatory changes in the levels of pro-inflammatory cytokines.

Disposition of intact liposomes of different compositions and of liposomal degradation products.

Small unilamellar liposomes containing bovine serum albumin were prepared by a new double-emulsion technique and administered to mice and rats in intravenous injections. The elimination of intact liposomes, the association of phospholipid marker with lipoproteins, and the appearance of released internal marker and its degradation products were followed by column chromatography of plasma samples. In vitro labelled lipoproteins were administered to the animals in intravenous injections together with free bovine serum albumin and the elimination of the two substances was studied by closely related techniques. The clearance of intact PC:PS (4:1) liposomes from plasma was biphasic and much faster than that of labelled lipoproteins and bovine serum albumin either originating from liposomes or injected as such. The second elimination phase for these liposomes was barely detectable by our analytical methods. In contrast, DSPC:CHOL (2:1) liposomes showed a very significant second-phase elimination, with a half-life of 12 hr for the intact liposomes. In tissue distribution studies in mice, the major accumulation of liposomal markers was found in the liver and spleen, and less in the kidneys and intestinal wall. Uptake into liver and spleen appeared to be due to the uptake of intact liposomes, whereas the uptake into kidneys and gut wall was caused by the uptake of liposomal degradation products. The uptake of PC:PS (4:1) liposomes into the liver was higher than that of DSPC:CHOL (2:1) liposomes; the opposite was the case with their uptake into the spleen. In rats, too, liposomes of different compositions showed significant variations in stability and in plasma half-lives of intact liposomes. Generally, there was a considerable increase in the liposomal stability in the presence of cholesterol and when use was made of a phospholipid with a high transition temperature.