title: Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases, yet current therapeutic treatments are inadequate due to a complex disease pathogenesis. The plant polyphenol apigenin has been shown to have anti-inflammatory and neuroprotective properties in a number of cell and animal models; however a comprehensive assessment has not been performed in a human model of AD. Here we have used a human induced pluripotent stem cell (iPSC) model of familial and sporadic AD, in addition to healthy controls, to assess the neuroprotective activity of apigenin. The iPSC-derived AD neurons demonstrated a hyper-excitable calcium signalling phenotype, elevated levels of nitrite, increased cytotoxicity and apoptosis, reduced neurite length and increased susceptibility to inflammatory stress challenge from activated murine microglia, in comparison to control neurons. We identified that apigenin has potent anti-inflammatory properties with the ability to protect neurites and cell viability by promoting a global down-regulation of cytokine and nitric oxide (NO) release in inflammatory cells. In addition, we show that apigenin is able to protect iPSC-derived AD neurons via multiple means by reducing the frequency of spontaneous Ca(2+) signals and significantly reducing caspase-3/7 mediated apoptosis. These data demonstrate the broad neuroprotective action of apigenin against AD pathogenesis in a human disease model.
authors: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors: Rachelle
authors: R
authors: Balez
authors: School of Medicine, Western Sydney University, Locked bag 1797, Penrith, NSW, Australia.
authors: Nicole
authors: N
authors: Steiner
authors: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors: Martin
authors: M
authors: Engel
authors: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors: Sonia Sanz
authors: SS
authors: Muñoz
authors: Illawarra Health and Medical Research Institute, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors: Jeremy Stephen
authors: JS
authors: Lum
authors: Illawarra Health and Medical Research Institute, School of Medicine, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors: Yizhen
authors: Y
authors: Wu
authors: CSIRO Informatics and Statistics, Locked Bag 17, North Ryde, NSW 1670, Australia.
authors: Dadong
authors: D
authors: Wang
authors: CSIRO Informatics and Statistics, Locked Bag 17, North Ryde, NSW 1670, Australia.
authors: Pascal
authors: P
authors: Vallotton
authors: Centre for Healthy Brain Ageing School of Medicine, University of New South Wales, High Street, Kensington,. NSW, 2052, Australia.
authors: Perminder
authors: P
authors: Sachdev
authors: School of Medicine, Western Sydney University, Locked bag 1797, Penrith, NSW, Australia.|Molecular Medicine Research Group, Western Sydney University, Locked bag 1797, Penrith, NSW, Australia.
authors: Michael
authors: M
authors: O'Connor
authors: Centre for Healthy Brain Ageing School of Medicine, University of New South Wales, High Street, Kensington,. NSW, 2052, Australia.
authors: Kuldip
authors: K
authors: Sidhu
authors: School of Medicine, Western Sydney University, Locked bag 1797, Penrith, NSW, Australia.|Centre of Complementary Medicine Research (CompleMed), Western Sydney University, Locked bag 1797, Penrith, NSW, Australia.
authors: Gerald
authors: G
authors: Münch
authors: Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Wollongong, NSW, 2522, Australia.
authors: Lezanne
authors: L
authors: Ooi
mesh_terms: D000328:Adult; D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020013:Calcium Signaling / Q000187:drug effects; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D047310:Apigenin; D007371:Interferon-gamma