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.
Highlights
Only a small amount of time and space
While epidemiological data indicate that non-steroidal anti-inflammatory drugs (NSAIDs) preferentially lower Alzheimer’s disease (AD) risk in APOE4 carriers[61,62], results from anti-inflammatory clinical trials indicate that drug efficacy will be highly context dependent
We developed a protocol for growth and extraction of high-yielding polyphenols from A. thaliana mutant seedlings
Summary
Only a small amount of time and space. polyphenol-enriched extracts can be and quickly obtained. Polyphenol extracts including curcumins, resveratrol and gallic acid derivatives reduce cytokine and chemokine responses in some AD models, the specific impact on neuroinflammation is still poorly understood[28,29,30,31,32,33,34,35,36]. Studies have demonstrated that dietary flavonoids preserve cognitive function during aging, and reduce the risk for AD and dementia[37,38,39,40]. A. thaliana mutants may provide a novel approach for producing extracts enriched in flavonoids and polyphenols. Three such mutants 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 LPS or oAβ. The plant-based aproach described may be of economic importance to produce an effective and viable product to target neuroinflammation, one of the earliest symptoms of AD, in a form of a nutraceutical or dietary supplement
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