BackgroundPlasmalogens (Pls) reportedly decreased in postmortem brain and in the blood of patients with Alzheimer's disease (AD). Recently we showed that intraperitoneal administration of Pls improved cognitive function in experimental animals. In the present trial, we tested the efficacy of oral administration of scallop-derived purified Pls with respect to cognitive function and blood Pls changes in patients with mild AD and mild cognitive impairment (MCI).MethodsThe study was a multicenter, randomized, double-blind, placebo-controlled trial of 24 weeks. Participants were 328 patients aged 60 to 85 years who had 20 to 27 points in Mini Mental State Examination-Japanese (MMSE-J) score and five or less points in Geriatric Depression Scale-Short Version-Japanese (GDS-S-J). They were randomized to receive either 1 mg/day of Pls purified from scallop or placebo. The patients and study physicians were masked to the assignment. The primary outcome was MMSE-J. The secondary outcomes included Wechsler Memory Scale-Revised (WMS-R), GDS-S-J and concentration of phosphatidyl ethanolamine plasmalogens (PlsPE) in erythrocyte membrane and plasma. This trial is registered with the University Hospital Medical Information Network, number UMIN000014945.FindingsOf 328 patients enrolled, 276 patients completed the trial (140 in the treatment group and 136 in the placebo group). In an intention-to-treat analysis including both mild AD (20 ≤ MMSE-J ≤ 23) and MCI (24 ≤ MMSE-J ≤ 27), no significant difference was shown between the treatment and placebo groups in the primary and secondary outcomes, with no severe adverse events in either group. In mild AD patients, WMS-R improved significantly in the treatment group, and the between group difference was nearly significant (P = 0.067). In a subgroup analysis of mild AD patients, WMS-R significantly improved among females and those aged below 77 years in the treatment group, and the between-group differences were statistically significant in females (P = 0.017) and in those aged below 77 years (P = 0.029). Patients with mild AD showed a significantly greater decrease in plasma PlsPE in the placebo group than in the treatment group.InterpretationOral administration of scallop-derived purified Pls may improve cognitive functions of mild AD.Funding.

BackgroundNeuroinflammation involves the activation of glial cells in neurodegenerative diseases such as Alzheimer’s disease (AD). Plasmalogens (Pls) are glycerophospholipids constituting cellular membranes and play significant roles in membrane fluidity and cellular processes such as vesicular fusion and signal transduction.MethodsIn this study the preventive effects of Pls on systemic lipopolysaccharide (LPS)-induced neuroinflammation were investigated using immunohistochemistry, real-time PCR methods and analysis of brain glycerophospholipid levels in adult mice.ResultsIntraperitoneal (i.p.) injections of LPS (250 μg/kg) for seven days resulted in increases in the number of Iba-1-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes in the prefrontal cortex (PFC) and hippocampus accompanied by the enhanced expression of IL-1β and TNF-α mRNAs. In addition, β-amyloid (Aβ3–16)-positive neurons appeared in the PFC and hippocampus of LPS-injected animals. The co-administration of Pls (i.p., 20 mg/kg) after daily LPS injections significantly attenuated both the activation of glial cells and the accumulation of Aβ proteins. Finally, the amount of Pls in the PFC and hippocampus decreased following the LPS injections and this reduction was suppressed by co-treatment with Pls.ConclusionsThese findings suggest that Pls have anti-neuroinflammatory and anti-amyloidogenic effects, thereby indicating the preventive or therapeutic application of Pls against AD.

Dietary sphingolipids (SL) inhibit colon carcinogenesis, reduce serum cholesterol, and improve skin barrier function and are considered to be "functional lipids". For comparative determination of the effects of SL with different chemical compositions on lipid metabolism and its related hepatic gene expression, Zucker fatty rats were fed pure sphingomyelin (SM) of animal origin and glucosylceramide (GC) of plant origin. After 45 days, the SM and GC diets led to significant reductions in hepatic lipid and plasma non-HDL cholesterol. Both SM and GC diets decreased plasma insulin levels, whereas only the GC diet increased the plasma adiponectin level. Hepatic gene expression analysis revealed increased expression of adiponectin receptor 2 (Adipor2), peroxisome proliferator-activated receptor alpha (PPARalpha), and pyruvate dehydrogenase kinase 4 (Pdk4). However, expression of stearoyl CoA desaturase (Scd1) was significantly decreased. These results suggest that dietary SL, even of different origins and chemical compositions, may prevent fatty liver and hypercholesterolemia through improvement of adiponectin signaling and consequent increases in insulin sensitivity.

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Neuroinflammation essentially involves an activation of glial cells as the cause/effect of neurodegenerative diseases such as Alzheimer's disease (AD). Plasmalogens (Pls) are glycerophospholipids constituting cellular membranes and play significant roles in membrane fluidity and cellular processes like vesicular fusion and signal transduction. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 250 μg/kg) for 7 days resulted in the morphological changes and increase in number of Iba-1(+) microglia showing neuroinflammation in the adult mouse hippocampus. The LPS-induced activation of glial cells was significantly attenuated by i.p. pretreatment with Pls dissolved in corn oil. In addition, systemic injection of LPS induced Aβ(1-16) (+) neurons in the hippocampus were also abolished by application of Pls. Finally, contents of Pls in the hippocampus decreased after LPS injection, and the reduction was suppressed by administration of Pls. These findings suggest an antiamyloidogenic effect of Pls, implicating a possible therapeutic application of Pls against AD.