P-191: Dietary DHA ameliorates amyloid-β and tau pathology via a mechanism involving presenilin 1 levels

AD patients have decreased serum and brain docosahexaenoic acid (DHA) compared to age-matched controls, suggesting that a deficiency in this polyunsaturated fatty acid (PUFA) could play a role in the disease. Furthermore, greater consumption of fish which contains DHA significantly reduces the likelihood of developing AD. We set out to evaluate the potential of dietary DHA, alone and in conjunction with arachidonic acid (ARA) or docosapentaenoic acid (DPA), as a preventative disease-modifying agent of AD pathology in a mouse model with both Aβ and tau pathology. 3 month old 3xTg-AD mice were treated with dietary PUFA containing diets for 3, 6 or 9 months. Mice were sacrificed and Aβ and tau pathology assessed by Western blot and sandwich ELISA. Soluble and intraneuronal Aβ was significantly decreased by ∼50% in DHA, DHA-DPA and DHA-ARA containing diets, while the insoluble and oligomeric Aβ pool remained unaltered after 3 months of treatment. Steady state levels of APP, C83 and C99 were also unaffected by dietary treatment, as were levels of BACE and ADAM10, and a number of putative Aβ degrading enzymes. Levels of presenilin 1 were reduced by 50% in the DHA, DHA-DPA and DHA-ARA groups, correlating with reduced soluble Aβ. Pathological somatodendritic accumulation of tau was also significantly reduced in the DHA, DHA-DPA and DHA-ARA groups, while phosphorylation was unaffected. With the longer dietary treatments only the DHA alone diet remained efficous at reducing both Aβ and tau pathology. Here we report the novel findings that dietary DHA-mediated reductions in soluble Aβ correlate with decreased steady state levels of PS1. Thus, the influence of DHA on Aβ levels is most likely mediated by a reduction in γ-secretase activity. In addition to the reduction in soluble and intraneuronal Aβ, dietary DHA also reduces steady state levels of tau, which accumulate in the somatodendritic compartments of neurons. Studies in aged humans should be conducted to assess how well PUFA supplementation translates from AD mouse models, as DHA-containing diets look very promising as potential therapeutic agents.