Neuroprotective effects of apigenin against inflammation, neuronal excitability and apoptosis in an induced pluripotent stem cell model of Alzheimer’s disease

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 Ca2+ 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.