Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model.
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.
Calon
Frédéric
F
Department of Medicine, University of California, Los Angeles, 90095, USA.
Lim
Giselle P
GP
Yang
Fusheng
F
Morihara
Takashi
T
Teter
Bruce
B
Ubeda
Oliver
O
Rostaing
Phillippe
P
Triller
Antoine
A
Salem
Norman
N
Ashe
Karen H
KH
Frautschy
Sally A
SA
Cole
Greg M
GM
D000199:Actins / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D004042:Dietary Fats, Unsaturated / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005526:Food, Formulated; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051025:bcl-Associated Death Protein
D000199:Actins; C494819:BAD protein, human; C494820:Bad protein, mouse; D002352:Carrier Proteins; D004042:Dietary Fats, Unsaturated; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D021122:Protein Subunits; D051025:bcl-Associated Death Protein; C053386:drebrins; D004281:Docosahexaenoic Acids; D019869:Phosphatidylinositol 3-Kinases