Open AccessArabidopsis thaliana extracts optimized for polyphenols production as potential therapeutics for the APOE-modulated neuroinflammation characteristic of Alzheimer’s disease in vitro
Author(s) -
Shivesh Ghura,
Leon M. Tai,
Ming Zhao,
Nicole Collins,
Chun Tao,
Katherine M. Warpeha,
Mary Jo LaDu
Publication year - 2016
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep29364
Subject(s) - neuroinflammation , apolipoprotein e , arabidopsis thaliana , biology , neurotoxin , chemistry , pharmacology , biochemistry , inflammation , medicine , immunology , mutant , disease , gene
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.