Abstract
Amyloid β(Aβ)1-42 fibrillation is a crucial step in the development of pathological hallmarks, such as neuritic plaques and neurofibrillary tangles, of Alzheimer’s disease (AD). In this study, we evaluated the effects of free docosahexaenoic acid (DHA), an essential brain polyunsaturated fatty acid (PUFA), on the inhibition of Aβ1-42 fibrillation by fluorescence correlation spectroscopy (FCS), a technique capable of detecting molecular movements and interactions in solution. We also examined whether free arachidonic acid (AA), eicosapentaenoic acid (EPA), and metabolites of DHA, including neuroprotectin D1 (NPD1, 10S, 17S-dihydroxy-DHA), resolvin D1 (RvD1, 7S, 8R, 17S-trihydroxy-DHA), and didocosahexaenoyl glycerol (diDHA), affect Aβ1-42 polymerization. The results of the FCS study reveal that DHA and AA significantly reduced the diffusion time of TAMRA (5-carboxytetramethylrhoda-mine)-Aβ1-42 by 28% and 31%, respectively, while EPA, NPD1, RvD1, and diDHA had no effects on diffusion time. These results indicate that DHA and AA inhibited Aβ1-42 polymerization and that their inhibitory effects occurred at the initial stage of Aβ1-42 polymerization. This study will advance the research on PUFAs in preventing AD progression.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid β (Aβ) peptides in neuritic plaques and neurofibrillar tangles in the affected brain regions [1]
Consistent with the findings of other studies [16,17,18,19], we have previously reported that Aβ1-42 fibrillation involves conformational changes from α helix to β sheet and passes through various phases of fibrillation, including the formation of dimers, trimers, tetramers, oligomers, and matured fibrils, using thioflavin T fluorospectroscopy, polyacrylamide gel electrophoresis (PAGE), western blot, fluorescence microscopy, and transmission electron microscopy [20,21,22,23]
Miwa et al / Advances in Alzheimer’s Disease 2 (2013) 66-72 the mechanism(s) of docosahexaenoic acid (DHA) action, we have previously shown that DHA inhibits in vitro Aβ1-42 fibrillation at the trimer/tetramer level, and thereby inhibits further progression of lateral stacking of these intermediates and prevents mature amyloid fibril formation [20,21]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by the deposition of amyloid β (Aβ) peptides in neuritic plaques and neurofibrillar tangles in the affected brain regions [1]. The natural plant compounds includeing curcumin, epigallocatechin-3-gallate and/or Ginkgo biloba extract and fish oil components such as docosahexaenoic acid (DHA) were reported to inhibit amyloid formation [24,25,26]. Among these compounds, DHA is the most abundant n-3 polyunsaturated fatty acid (PUFA) in the mammalian brain [27,28,29], and deficiency of DHA is associated with memory impairment in AD model rats [30] and AD patients [31].
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