title: Maysin and Its Flavonoid Derivative from Centipedegrass Attenuates Amyloid Plaques by Inducting Humoral Immune Response with Th2 Skewed Cytokine Response in the Tg (APPswe, PS1dE9) Alzheimer's Mouse Model.
abstract: Alzheimer's disease (AD) is a slow, progressive neurodegenerative disease and the most common type of dementia in the elderly. The etiology of AD and its underlying mechanism are still not clear. In a previous study, we found that an ethyl acetate extract of Centipedegrass (CG) (i.e., EA-CG) contained 4 types of Maysin derivatives, including Luteolin, Isoorientin, Rhamnosylisoorientin, and Derhamnosylmaysin, and showed protective effects against Amyloid beta (Aβ) by inhibiting oligomeric Aβ in cellular and in vitro models. Here, we examined the preventative effects of EA-CG treatment on the Aβ burden in the Tg (Mo/Hu APPswe PS1dE9) AD mouse model. We have investigated the EA-CG efficacy as novel anti-AD likely preventing amyloid plaques using immunofluorescence staining to visually analyze Aβ40/42 and fibril formation with Thioflavin-S or 6E10 which are the profile of immunoreactivity against epitope Aβ1-16 or neuritic plaque, the quantitation of humoral immune response against Aβ, and the inflammatory cytokine responses (Th1 and Th2) using ELISA and QRT-PCR. To minimize the toxicity of the extracted CG, we addressed the liver toxicity in response to the CG extract treatment in Tg mice using relevant markers, such as aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) measurements in serum. The EA-CG extract significantly reduced the Aβ burden, the concentration of soluble Aβ40/42 protein, and fibril formation in the hippocampus and cortex of the Tg mice treated with EA-CG (50 mg/kg BW/day) for 6 months compared with the Tg mice treated with a normal diet. Additionally, the profile of anti-inflammatory cytokines revealed that the levels of Th2 (interleukin-4 (IL-4) and interleukin-10 (IL-10)) cytokines are more significantly increased than Th1 (interferon-γ (IFN-γ), interleukin-2(IL-2)) in the sera. These results suggest that the EA-CG fraction induces IL-4/IL-10-dependent anti-inflammatory cytokines (Th2) rather than pro-inflammatory cytokines (Th1), which are driven by IL-2/IFN-γ. With regard to the immune response, EA-CG induced an immunoglobulin IgG and IgM response against the EA-CG treatment in the Tg mice. Furthermore, EA-CG significantly ameliorated the level of soluble Aβ42 and Aβ40. Similarly, we observed that the fibril formation was also decreased by EA-CG treatment in the hippocampus and cortex after quantitative analysis with Thioflavin-S staining in the Tg brain tissues. Taken together, our findings suggested that Maysin and its derivative flavonoid compounds in the EA-CG fraction might be beneficial therapeutic treatments or alternative preventative measures to adjuvant for boosting humoral and cellular include immune response and anti-inflammation which may lead to amyloid plaque accumulation in Alzheimer's patients' brains.
authors.affiliation: Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea.
authors.forename: Yuno
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Environmental Health Science, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Kim
authors.affiliation: Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea.
authors.forename: Min-Kwon
authors.initials: MK
authors.lastname: Lee
authors.affiliation: Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea.
authors.forename: Il-Hwa
authors.initials: IH
authors.lastname: Hong
authors.affiliation: Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea.
authors.forename: Chung-Kil
authors.initials: CK
authors.lastname: Won
authors.affiliation: Advanced Radiation Technology Institute, Korea Atomic Energy Institute, Jeongeup, Korea.
authors.forename: Hyoung-Woo
authors.initials: HW
authors.lastname: Bai
authors.affiliation: Advanced Radiation Technology Institute, Korea Atomic Energy Institute, Jeongeup, Korea.
authors.forename: Seung Sik
authors.initials: SS
authors.lastname: Lee
authors.affiliation: Advanced Radiation Technology Institute, Korea Atomic Energy Institute, Jeongeup, Korea.
authors.forename: SungBeom
authors.initials: S
authors.lastname: Lee
authors.affiliation: Advanced Radiation Technology Institute, Korea Atomic Energy Institute, Jeongeup, Korea.
authors.forename: Byung Yeoup
authors.initials: BY
authors.lastname: Chung
authors.affiliation: Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, Korea.
authors.forename: Jae-Hyeon
authors.initials: JH
authors.lastname: Cho
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D005419:Flavonoids / Q000494:pharmacology*; D005960:Glucosides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology*; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D016207:Cytokines; D005419:Flavonoids; D005960:Glucosides; D010446:Peptide Fragments; D010936:Plant Extracts; C538897:amyloid beta-protein (40-42); C114429:maysin