title: Omega-3 Fatty Acids Augment the Actions of Nuclear Receptor Agonists in a Mouse Model of Alzheimer's Disease.
abstract: Alzheimer's disease (AD) is a highly prevalent disorder for which there are no effective therapies. Accumulation of amyloid β (Aβ) peptides in the brain is associated with impaired cognition and memory, pronounced inflammatory dysregulation, and subsequent amyloid plaque deposition. Thus, drugs that promote the clearance of Aβ peptides and resolution of inflammation may represent viable therapeutic approaches. Agonists of nuclear receptors LXR:RXR and PPAR:RXR act to ameliorate AD-related cognitive impairment and amyloid accumulation in murine models of AD. The use of an agonist to the nuclear receptor RXR, bexarotene, as monotherapy against AD, presents potential challenges due to the metabolic perturbations it induces in the periphery, most prominently hypertriglyceridemia. We report that the ω-3 fatty acid docosahexaenoic acid (DHA), in combination with bexarotene, enhances LXR:RXR target gene expression of Abca1 and ApoE, reduces soluble forms of Aβ, and abrogates release of pro-inflammatory cytokines and mediators both in vitro and in a mouse model of AD. Moreover, DHA abrogates bexarotene-induced hypertriglyceridemia in vivo. Importantly, dual therapy promotes reductions in AD pathology and resultant amelioration of cognitive deficits. While monotherapy with either bexarotene or DHA resulted in modest effects in vitro and in vivo, combined treatment with both agents produced a significant additive benefit on associated AD-related phenotypes, suggesting that targeted combinatorial agents may be beneficial over single agents alone in treating AD.
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Brad T
authors.initials: BT
authors.lastname: Casali
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Angela W
authors.initials: AW
authors.lastname: Corona
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Mariani
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: J Colleen
authors.initials: JC
authors.lastname: Karlo
authors.affiliation: ReXceptor, Cleveland, Ohio 44106.
authors.forename: Kaushik
authors.initials: K
authors.lastname: Ghosal
authors.affiliation: Alzheimer Research Laboratory, Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and gel2@case.edu.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Landreth
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000077610:Bexarotene; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*
chemical_list: D015525:Fatty Acids, Omega-3; D018160:Receptors, Cytoplasmic and Nuclear; D013764:Tetrahydronaphthalenes; D004281:Docosahexaenoic Acids; D000077610:Bexarotene
keywords: 5XFAD; ABCA1; ApoE; bexarotene; inflammation; omega-3 fatty acids