Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model

Frédéric Calon, Giselle P. Lim, Fusheng Yang, Takashi Morihara, Bruce Teter, Oliver Ubeda, Phillippe Rostaing, Antoine Triller, Norman Salem, Karen H. Ashe, Sally A. Frautschy, Greg M. Cole

Research output: Contribution to journalArticlepeer-review

595 Scopus citations

Abstract

Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85α subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. N-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD.

Original languageEnglish (US)
Pages (from-to)633-645
Number of pages13
JournalNeuron
Volume43
Issue number5
DOIs
StatePublished - Sep 2 2004

Bibliographical note

Funding Information:
We thank the patients and families who generously donated brain tissue samples for this research via the Neuropathology and Molecular Genetics Core of the UCLA ADRC (H. Vinters, P50 AG 16570) and the USC neuropathology ADRC core (Dr. C.A. Miller [P50 AG05142]). We also thank Ping Ping Chen, Peter Kim, and Mychica Simmons for technical expertise. This work was supported by a VA Merit (G.M.C.) and NIH grants RO1 AG13741, NS43946 (G.M.C.), AG10685, and AG16793 (S.A.F.), UCLA ADRC (PO1 AG16570, G.M.C. and S.A.F.), and a Senior Research Fellowship from the Canadian Institutes of Health Research (F.C.).

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