Oral Administration of Ethanolamine Glycerophospholipid Containing a High Level of Plasmalogen Improves Memory Impairment in Amyloid ß-Infused Rats.

Ethanolamine plasmalogen (PlsEtn), a major phospholipid in neuronal membranes [60-90 mol% of ethanolamine glycerophospholipid (EtnGpl)], is specifically decreased in brains from patients with Alzheimer's disease (AD). The present study investigated how PlsEtn administration affects cognitive deficits and lipid composition in an animal model of AD. AD model rats were infused with amyloid-ß (Aß) into the cerebral ventricle and divided into three groups. Control, Egg, and Ascidian groups were then orally administered vehicle, egg yolk EtnGpl (260 µmol as EtnGpl/kg BW/day; 10 µmol as PlsEtn/kg BW/day), or ascidian viscera EtnGpl (260 µmol as EtnGpl/kg BW/day; 209 µmol as PlsEtn/kg BW/day), respectively. After 4 weeks of dosing, Aß-infused rats were tested for learning ability in an 8-arm radial maze. The administration of ascidian viscera EtnGpl improved both reference and working memory-related learning abilities. In lipid analysis, the Ascidian group showed higher levels of PlsEtn species in the plasma, erythrocytes, and liver when compared to other groups. In addition, although there were no differences at levels of total plasmalogen including choline plasmalogen, the Ascidian group had significantly higher levels of 18:0ol/22:6-PlsEtn in the cerebral cortex. These levels of 18:0ol/22:6-PlsEtn in the cerebral cortex were correlated with working memory-related learning ability. Moreover, 18:0ol/22:6-PlsEtn levels in the cerebral cortex showed positive correlations with those in the erythrocytes and liver. In summary, dietary PlsEtn, especially that with 22:6n-3 (docosahexaenoic acid, DHA), may ameliorate learning deficiencies in AD by altering lipid composition in the brain.

Protective effects of prescription n-3 fatty acids against impairment of spatial cognitive learning ability in amyloid ß-infused rats.

Deposition of amyloid ß peptide (Aß) into the brain causes cognitive impairment. We investigated whether prescription pre-administration of n-3 fatty acids improves cognitive learning ability in young rats and whether it protects against learning ability impairments in an animal model of Alzheimer's disease that was prepared by infusion of Aß(1-40) into the cerebral ventricles of rats. Pre-administration of TAK-085 (highly purified and concentrated n-3 fatty acids containing eicosapentaenoic acid ethyl ester and docosahexaenoic acid ethyl ester) at 300 mg kg(-1) day(-1) for 12 weeks significantly reduced the number of reference memory errors in an 8-arm radial maze, suggesting that long-term administration of TAK-085 improves cognitive leaning ability in rats. After pre-administration, the control group was divided into the vehicle and Aß-infused groups, whereas the TAK-085 pre-administration group was divided into the TAK-085 and TAK-085 + Aß groups (TAK-085-pre-administered Aß-infused rats). Aß(1-40) or vehicle was infused into the cerebral ventricle using a mini osmotic pump. Pre-administration of TAK-085 to the Aß-infused rats significantly suppressed the number of reference and working memory errors and decreased the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and hippocampus of Aß-infused rats, suggesting that TAK-085 increases antioxidative defenses. The present study suggests that long-term administration of TAK-085 is a possible therapeutic agent for protecting against Alzheimer's disease-induced learning deficiencies.

Nobiletin restoring beta-amyloid-impaired CREB phosphorylation rescues memory deterioration in Alzheimer's disease model rats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive and memory deterioration. Production and accumulation of beta-amyloid peptide (Abeta) is central to the pathogenesis of AD. Recent studies have demonstrated that PKA/CREB-dependent signaling pathway and long-term potentiation are inhibited by sublethal concentrations of Abeta(1-42) in cultured hippocampus neurons. Here, we examined the effects of nobiletin on the Abeta-induced inhibition of CREB phosphorylation in cultured rat hippocampus neurons. A sublethal concentration of Abeta(1-42) or Abeta(1-40) decreased glutamate-induced CREB phosphorylation, whereas pretreatment with nobiletin reversed the Abeta-induced decrease in CREB phosphorylation. The effects of nobiletin on impairment of learning ability were also examined in chronically Abeta(1-40) infused AD model rats using the eight-arm radial maze. In the AD model rats, nobiletin showed protective effects on Abeta(1-40)-induced impairment of learning ability. These results suggest that nobiletin has the potential for becoming a novel lead compound for drug development for AD.