title: Arabidopsis thaliana extracts optimized for polyphenols production as potential therapeutics for the APOE-modulated neuroinflammation characteristic of Alzheimer's disease in vitro.
abstract: Although the cause of Alzheimer's disease (AD) is unknown, glial-induced neuroinflammation is an early symptom. Familial AD is caused by increases in amyloid-beta (Aβ) peptide, particularly soluble oligomeric (oAβ), considered a proximal neurotoxin and neuroinflammatory stimuli. APOE4, a naturally occurring genotype of APOE, is the greatest genetic risk factor for AD; increasing risk up to 12-fold compared to APOE3 and APOE2. oAβ-induced neuroinflammation is greater with APOE4 compared to APOE3 and APOE2. As sinapates and flavonoids have anti-inflammatory properties, a protocol was developed for optimizing polyphenol production in seedlings of Arabidopsis thaliana (A. thaliana). Three mutants (cop1, prn1, xpf3) were identified, and the extracts treated with liver microsomes to mimic physiological metabolism, with HPLC and MS performed on the resulting metabolites for peak identification. These extracts were used to treat primary glial cells isolated from human APOE-targeted-replacement (APOE-TR) and APOE-knock-out (KO) mice, with neuroinflammation induced by lipopolysaccharide (LPS) or oAβ. The dose-response data for TNFα secretion demonstrate the followed the order: APOE-KO > APOE4 > APOE3 > APOE2, with xpf3 the most effective anti-neuroinflammatory across APOE genotypes. Thus, the plant-based approach described herein may be particularly valuable in treating the APOE4-induced neuroinflammatory component of AD risk.
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Shivesh
authors.initials: S
authors.lastname: Ghura
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Tai
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Collins
authors.affiliation: Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Chun-Tao
authors.initials: CT
authors.lastname: Che
authors.affiliation: Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Warpeha
authors.affiliation: Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: LaDu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001057:Apolipoproteins E / Q000009:adverse effects* / Q000235:genetics; D017360:Arabidopsis / Q000378:metabolism* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D010936:Plant Extracts / Q000378:metabolism* / Q000494:pharmacology; D059808:Polyphenols / Q000096:biosynthesis* / Q000627:therapeutic use*; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D001057:Apolipoproteins E; D008070:Lipopolysaccharides; D010936:Plant Extracts; D059808:Polyphenols; D016211:Transforming Growth Factor alpha