title: Dietary DHA supplementation in an APP/PS1 transgenic rat model of AD reduces behavioral and Aβ pathology and modulates Aβ oligomerization.
abstract: Increased dietary consumption of docosahexaenoic acid (DHA) is associated with decreased risk for Alzheimer's disease (AD). These effects have been postulated to arise from DHA's pleiotropic effects on AD pathophysiology, including its effects on β-amyloid (Aβ) production, aggregation, and toxicity. While in vitro studies suggest that DHA may inhibit and reverse the formation of toxic Aβ oligomers, it remains uncertain whether these mechanisms operate in vivo at the physiological concentrations of DHA attainable through dietary supplementation. We sought to clarify the effects of dietary DHA supplementation on Aβ indices in a transgenic APP/PS1 rat model of AD. Animals maintained on a DHA-supplemented diet exhibited reductions in hippocampal Aβ plaque density and modest improvements on behavioral testing relative to those maintained on a DHA-depleted diet. However, DHA supplementation also increased overall soluble Aβ oligomer levels in the hippocampus. Further quantification of specific conformational populations of Aβ oligomers indicated that DHA supplementation increased fibrillar (i.e. putatively less toxic) Aβ oligomers and decreased prefibrillar (i.e. putatively more toxic) Aβ oligomers. These results provide in vivo evidence suggesting that DHA can modulate Aβ aggregation by stabilizing soluble fibrillar Aβ oligomers and thus reduce the formation of both Aβ plaques and prefibrillar Aβ oligomers. However, since fibrillar Aβ oligomers still retain inherent neurotoxicity, DHA may need to be combined with other interventions that can additionally reduce fibrillar Aβ oligomer levels for more effective prevention of AD in clinical settings.
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA. Electronic address: eteng@ucla.edu.
authors.forename: Edmond
authors.initials: E
authors.lastname: Teng
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Taylor
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Tina
authors.initials: T
authors.lastname: Bilousova
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Weiland
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Thaidan
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA; Department of Neurobiology and Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zuo
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Chen
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA; Biochemistry Department and Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Glabe
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Takacs
authors.affiliation: Retina Foundation of the Southwest, Dallas, TX, USA; Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Hoffman
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Frautschy
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cole
mesh_terms: D000544:Alzheimer Disease / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids; D005260:Female; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D018782:Maze Learning; D010446:Peptide Fragments / Q000378:metabolism*; D058225:Plaque, Amyloid / Q000178:diet therapy* / Q000378:metabolism / Q000473:pathology / Q000523:psychology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D016896:Treatment Outcome
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D004281:Docosahexaenoic Acids
keywords: Aggregation; Alzheimer's disease; Docosahexaenoic acid; Fibrillar; Hippocampus; Oligomers; Prefibrillar; Transgenic; β-amyloid