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PNAS 102 (31): 10858-10863

Copyright © 2005 by the National Academy of Sciences.


BIOCHEMISTRY

Docosahexaenoic acid: A positive modulator of Akt signaling in neuronal survival

Mohammed Akbar, Frances Calderon, Zhiming Wen, and Hee-Yong Kim *

Section of Mass Spectrometry, Laboratory of Membrane Biochemistry and Biophysics, National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20952-8115

Edited by Thomas C. Südhof, University of Texas Southwestern Medical Center, Dallas, TX

Accepted for publication June 8, 2005.

Received for publication April 7, 2005.

Abstract: Phosphatidylinositol 3-kinase [PI (3)K]/Akt signaling is a critical pathway in cell survival. Here, we demonstrate a mechanism where membrane alteration by the n-3 fatty acid status affects Akt signaling, impacting neuronal survival. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid highly enriched in neuronal membranes, promotes neuronal survival by facilitating membrane translocation/activation of Akt through its capacity to increase phosphatidylserine (PS), the major acidic phospholipid in cell membranes. The activation of PI (3)K and phosphatidylsinositol triphosphate formation were not affected by DHA, indicating that membrane interaction of Akt is the event responsible for the DHA effect. Docosapentaenoic acid, which replaces DHA during n-3 fatty acid deficiency, was less effective in accumulating PS and translocating Akt and thus less effective in preventing apoptosis. Consistently, in vivo reduction of DHA by dietary depletion of n-3 fatty acids decreased hippocampal PS and increased neuronal susceptibility to apoptosis in cultures. This mechanism may contribute to neurological deficits associated with n-3 fatty acid deficiency and support protective effects of DHA in pathological models such as brain ischemia or Alzheimer's disease.

Key Words: apoptosis • phosphatidylserine • hippocampus • docosapentaenoic acid • n-3 fatty acid deficiency


Author contributions: H.-Y.K. designed research; M.A., F.C., and Z.W. performed research; M.A., F.C., Z.W., and H.-Y.K. analyzed data; and M.A., F.C., and H.-Y.K. wrote the paper.

This paper was submitted directly (Track II) to the PNAS office.

Abbreviations: DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; PS, phosphatidylserine; PI, phosphatidylinositol; PIP, phosphatidylsinositol phosphate; PIP3, phosphatidylinositol triphosphate; PI (3)K, phosphatidylinositol 3-kinase; IGF, insulin growth factor; PH domain, pleckstrin homology domain.

* To whom correspondence should be addressed. E-mail: hykim{at}mail.nih.gov.


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