Alpha-Linolenic Acid from Perilla frutescens var. japonica Oil Protects A beta-Induced Cognitive Impairment through Regulation of APP Processing and A beta Degradation

Abstract

Alzheimer's disease (AD) is characterized by progressive cognitive and memory impairment. The major pathological hallmark of AD is the accumulation of amyloid beta (A beta), which is produced from the amyloid precursor protein (APP) through cleavage of beta- and gamma-secretase. Recently, dietary plant oil containing omega-3 polyunsaturated fatty acid has become an attractive alternative source to fish oil containing eicosapentaenoic acid or docosahexaenoic acid (DHA). We investigated whether ALA isolated from perilla oil has direct effects on improvement of cognitive ability and molecular mechanisms in APP processing in comparison with DHA. In the present study, ICR mice were treated orally with ALA or DHA (100 mg/kg/day) for 14 days after i.c.v. injection of A beta(25-35). Administration of ALA resulted in a prevention of learning and memory deficit in A beta(25-35)-injected mice compared with the control group, as observed in T-maze, novel object recognition, and Morris water maze tests. ALA supplementation also markedly ameliorated the A beta(25-35)-induced, oxidative stress by inhibition of lipid peroxidation and nitric oxide overproduction in the mouse brain, liver, and kidney, almost down to the levels in DHA-administered group. These effects of ALA on protective mechanisms were related to the regulation of APP processing via promoting nonamyloidogenic pathway such as up-regulation of soluble APP alpha, C-terminal fragment alpha/beta ratio, and A disintegrin and metalloprotease10 protein expressions. Furthermore, ALA inhibited the amyloidogenic pathway through the down-regulation of beta-site APP-cleaving enzyme and presenilin2. ALA also enhanced A beta degradation enzyme, insulin-degrading enzyme. In conclusion, the present study indicated a beneficial effect of ALA in improving the cognitive ability against A beta(25-35), and these effects were comparable to those exerted by DHA. Its neuroprotective effects are mediated, in part, by regulation of APP processing and A beta degradation, and thus, ALA might be a potential candidate for prevention or treatment of neurodegenerative diseases such as AD.