Dietary Docosahexaenoic Acid and Docosapentaenoic Acid Ameliorate Amyloid-β and Tau Pathology via a Mechanism Involving Presenilin 1 Levels

Abstract

The underlying cause of sporadic Alzheimer disease (AD) is unknown, but a number of environmental and genetic factors are likely to be involved. One environmental factor that is increasingly being recognized as contributing to brain aging is diet, which has evolved markedly over modern history. Here we show that dietary supplementation with docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, in the 3xTg-AD mouse model of AD reduced the intraneuronal accumulation of both amyloid-␤ (A␤) and tau. In contrast, combining DHA with n-6 fatty acids, either arachidonic acid or docosapentaenoic acid (DPAn-6), diminished the efficacy of DHA over a 12 month period. Here we report the novel finding that the mechanism accounting for the reduction in soluble A␤ was attributable to a decrease in steady-state levels of presenilin 1, and not to altered processing of the amyloid precursor protein by either the ␣-or ␤-secretase. Furthermore, the presence of DPAn-6 in the diet reduced levels of early-stage phospho-tau epitopes, which correlated with a reduction in phosphorylated c-Jun N-terminal kinase, a putative tau kinase. Collectively, these results suggest that DHA and DPAn-6 supplementations could be a beneficial natural therapy for AD.

-Amyloid Oligomers Induce Phosphorylation of Tau and Inactivation of Insulin Receptor Substrate via c-Jun N-Terminal Kinase Signaling: Suppression by Omega-3 Fatty Acids and Curcumin

“…Our own and previous work from other groups indicate that dietary DHA significantly improves cognitive deficits, protects from synaptic protein loss, and lowers insoluble A␤ in transgenic AD mouse models (Calon et al, 2004;Lim et al, 2005;Oksman et al, 2006;Ma et al, 2007). Our current data are consistent with a report that algal DHA reduced A␤ accumulation, suggesting this effect may have reduced JNK activation and ptau in 3xTg-AD mice (Green et al, 2007), but the effects we observed need not be secondary to A␤ reduction because we show that DHA reduces the JNK, IRS-1, and tau phosphorylation response to exogenous A␤ oligomers. Both protective activities are likely, but we did not find robust A␤ labeling at 9 months in the line of 3xTg-AD mice on the diets used.…”

n−3 fatty acids prevent impairment of neurogenesis and synaptic plasticity in B-cell activating factor (BAFF) transgenic mice

“…This form of LTP depends upon mature granule neurons synaptic activity (Saxe et al, 2006). The modulation of PICRO-LTP might be due to the blockage of hippocampal microglia activation as previously reported in different animal models (Calon et al, 2005) (Green et al, 2007) (Fig. 4).…”

Nutrition, Brain Aging, and Neurodegeneration: Table 1.

“…Similarly, DHA reduced amyloid ␤ 42 (A␤42) in AD mice (Lim et al, 2005;Oksman et al, 2006;Green et al, 2007;Hooijmans et al, 2007) and production by cultured human neurons (Lukiw et al, 2005). The mechanism involved in the DHAinduced reductions in A␤42 may be due to multiple effects, such as: changes in lipid raft structure (Stillwell et al, 2005), alterations in APP processing (Ehehalt et al, 2003), induction of antiamyloidogenic chaperones for APP , and A␤ transthyretin (Schwarzman et al, 1994;Puskás et al, 2003).…”