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 p85alpha 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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / metabolism
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Alzheimer Disease / metabolism*
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Alzheimer Disease / pathology
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Alzheimer Disease / prevention & control*
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Brain / drug effects
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Brain / metabolism*
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Brain / pathology
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Carrier Proteins / drug effects
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Carrier Proteins / metabolism
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Dendrites / drug effects*
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Dendrites / metabolism*
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Dendrites / pathology
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Dietary Fats, Unsaturated / metabolism
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Dietary Fats, Unsaturated / pharmacology
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Disease Models, Animal
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Docosahexaenoic Acids / metabolism
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Docosahexaenoic Acids / pharmacology*
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Docosahexaenoic Acids / therapeutic use
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Down-Regulation / genetics
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Female
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Food, Formulated
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Humans
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Male
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Mice
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Mice, Transgenic
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Microscopy, Electron
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Nerve Tissue Proteins / metabolism
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Neuropeptides / metabolism
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Oxidative Stress / drug effects
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Oxidative Stress / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Protein Subunits / metabolism
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Synapses / drug effects
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Synapses / metabolism
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Synapses / pathology
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bcl-Associated Death Protein
Substances
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Actins
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BAD protein, human
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Bad protein, mouse
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Carrier Proteins
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Dietary Fats, Unsaturated
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Nerve Tissue Proteins
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Neuropeptides
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Protein Subunits
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bcl-Associated Death Protein
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drebrins
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Docosahexaenoic Acids
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Phosphatidylinositol 3-Kinases