High fat diet induces brain injury and neuronal apoptosis via down-regulating 3-β hydroxycholesterol 24 reductase (DHCR24)

Abstract Hyperlipidemia (HLP) plays an important role in the pathogenesis of Alzheimer’s disease (AD). However, its pathological molecular mechanism remained unclear. 3β-hydroxysterol Δ24- reductase (DHCR24), a key enzyme in the last step of cholesterol synthesis, has been reported to decrease in the affected areas in the brain of AD patients. In this study, hyperlipidemic mouse model was established to study the effect of high blood lipid on brain. The data obtained from HPLC analysis demonstrated that the cholesterol level in brain of mice with hyperlipidemia was noticeably elevated compared to the control conditions. While the pathological damages were observed in both cerebral cortex and hippocampus in the brain of hyperlipidemic mice. Furthermore, the protein level of DHCR24 was downregulated accompanied by elevated ubiquitination level in the hyperlipidemic mice brain. The mouse neuroblastoma cells N2a were exposed to the excess cholesterol loading, the cells underwent apoptosis and the gene and protein of DHCR24 in cholesterol-loaded N2a cells were significantly reduced. In addition, the golden indexes of endoplasmic reticulum stress, BOP and ROP, increased significantly in response to the cholesterol loading. More importantly, overexpression of DHCR24 in N2a reversed neuronal apoptosis induced by the cholesterol loading. Conclusively, these findings suggested that hyperlipidemia could cause brain tissue injuries via down-regulating DHCR24, and overexpression of DHCR24 may alleviate hyperlipidemia-induced neuronal cells damage by reversing the endoplasmic reticulum stress-mediated apoptosis.