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The Journal of Neuroscience, April 18, 2007, 27(16):4385-4395; doi:10.1523/JNEUROSCI.0055-07.2007

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Neurobiology of Disease
Dietary Docosahexaenoic Acid and Docosapentaenoic Acid Ameliorate Amyloid-ß and Tau Pathology via a Mechanism Involving Presenilin 1 Levels

Kim N. Green,¹ Hilda Martinez-Coria,¹ Hasan Khashwji,¹ Eileen B. Hall,² Karin A. Yurko-Mauro,² Lorie Ellis,² and Frank M. LaFerla¹

¹Department of Neurobiology and Behavior, University of California, Irvine, California 92697-4545, and ²Martek Biosciences Corporation, Columbia, Maryland 21045

Correspondence should be addressed to Dr. Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla{at}uci.edu

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-ß (Aß) 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 Aß 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 ß-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.

Key words: tau; Alzheimer's; docosahexanoic acid; docosapentaenoic acid; presenilin; amyloid; transgenic

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Received Sept. 20, 2006; revised Feb. 15, 2007; accepted March 16, 2007.

Correspondence should be addressed to Dr. Frank M. LaFerla, Department of Neurobiology and Behavior, University of California, Irvine, 1109 Gillespie Neuroscience Building, Irvine, CA 92697-4545. Email: laferla{at}uci.edu

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