Role of vitamin D mediated signaling in iron‐induced neurodegeneration: Implications in the pathogenesis of Alzheimer's disease

Abstract

AbstractBackgroundThe neurodegeneration of sporadic Alzheimer's disease (AD) has several environmental, metabolic and endocrine components. Results of post‐mortem analysis of increased iron accumulation in AD brain and various epidemiological studies indicating association of AD with vitamin D insufficiency, prompted us to examine the role of vitamin D signaling in an experimental model of neurodegeneration induced by iron on undifferentiated SHSY5Y cells.MethodSHSY5Y cells were exposed to ferric ammonium citrate (FAC, 25‐ 400 μM) with or without 1,25 dihydroxyvitamin D for 24 ‐ 48 h followed by the measurements of oxidative damage markers, mitochondrial functional status, APP, BACE expressions and cell death parameters. Separately similar parameters were assessed in SHHSY5Y cells where vitamin D receptor VDR expression was knocked down by specific siRNA.ResultWe observed that vitamin D ameliorated various features of FAC induced cytotoxicity such as oxidative damage, mitochondrial membrane depolarization, impaired ATP synthesis and loss of cell viability. Exposure of SHSY5Y cells to FAC resulted in elevated APP and BACE mRNA levels which could be prevented by 1,25 dihydroxyvitamin D. Iron caused differential effects on VDR mRNA and protein expression levels in SHSY5Y cells; an increase in mRNA but a decrease in protein expressions. The iron effects were significantly prevented by co‐treatment with 1,25 dihydroxyvitamin D. The effects of VDR knock‐down on both control and FAC‐ treated cells showed augmented cell death with significant mitochondrial dysfunction, lipid peroxidation and oxidative damage.ConclusionOur experimental data suggest that vitamin D and VDR mediated signaling is integral in cell survival under basal condition as well as during iron‐induced cytotoxicity. The results have implications in the context of NBIA in aging and the pathogenesis of AD.