Investigating the effect of human apolipoprotein E isoforms on expression level of CLS and MINO genes involved in mitochondrial function in transgenic Drosophila model

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by aberrant lipid metabolism and mitochondrial dysfunction, features related to mitochondria-associated ER membranes (MAM). ApoE is recognized as the major AD risk factor. Human ApoE has three isoforms including Apoε2, Apoε3 and Apoε4. It has revealed that ε4 allele carriers are at higher risk of developing AD than ε3 allele carriers. Given that Apoε4 is a major AD risk factor and that MAM dysfunction in lipid metabolism may affect mitochondrial function, we assessed the expression pattern of cardiolipin synthetase (CLS) and glycerol-3-phosphate acyltransferase 2 (MINO) genes in Drosophila model of AD. To the best of our knowledge, this is the first study to investigate the effect of ApoE isoforms on mitochondrial function in Drosophila model of AD. RNA extraction was performed using glazt2a.gal4.UAS.hapoe transgenic flies harboring Apoε isoforms. Following cDNA synthesis, mRNA expression levels of target (CLS and MINO) and housekeeping (eEF1α) genes were measured by qRT-PCR. Our results did not show a significant decrease in CLS and MINO expression level in Apoɛ3 and Apoɛ4 groups as compared to the control. Although this reduction was not statistically significant, the decreasing trend indicates a kind of disruption in lipid biosynthesis and may directly affect mitochondrial function. Though the impact of Apoɛ4 on AD pathogenesis has been elucidated, the exact mechanism through which Apoɛ4 mediates AD progression is still unknown. Investigating the biology of ApoE isoforms using both human and AD animal models is recommended.