Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and A beta pathology and modulates A beta oligomerization

摘要

Increased dietary consumption of docosahexaenoic acid (DHA) is associated with decreased risk for Alzheimer's disease (AD). These effects have been postulated to arise from DHA's pleiotropic effects on AD pathophysiology, including its effects on beta-amyloid (A beta) production, aggregation, and toxicity. While in vitro studies suggest that DHA may inhibit and reverse the formation of toxic A beta oligomers, it remains uncertain whether these mechanisms operate in vivo at the physiological concentrations of DHA attainable through dietary supplementation. We sought to clarify the effects of dietary DHA supplementation on A beta indices in a transgenic APP/PS1 rat model of AD. Animals maintained on a DHA-supplemented diet exhibited reductions in hippocampal A beta plaque density and modest improvements on behavioral testing relative to those maintained on a DHA-depleted diet. However, DHA supplementation also increased overall soluble A beta oligomer levels in the hippocampus. Further quantification of specific conformational populations of A beta oligomers indicated that DHA supplementation increased fibrillar (i.e. putatively less toxic) A beta oligomers and decreased prefibrillar (i.e. putatively more toxic) A beta oligomers. These results provide in vivo evidence suggesting that DHA can modulate A beta aggregation by stabilizing soluble fibrillar A beta oligomers and thus reduce the formation of both A beta plaques and prefibrillar AS oligomers. However, since fibrillar A beta oligomers still retain inherent neurotoxicity, DHA may need to be combined with other interventions that can additionally reduce fibrillar A beta oligomer levels for more effective prevention of AD in clinical settings. Published by Elsevier Inc.