SREBP‐2 Activation is Independent of FPP Levels in Neural Cells

Abstract

Listen

Translate article

We recently reported that FPP and GGPP levels and gene expression of FPP synthase and GGPP synthase were significantly elevated in frontal cortex gray and white matter of Alzheimer disease patients as compared with normal neurological controls whereas cholesterol levels and HMG‐CoA reductase gene expression were unchanged. Stimulation of FPP synthase gene expression can occur with the binding of the transcription factor sterol regulatory element binding protein‐2 (SREBP‐2). Activation of the SREBP pathway is induced by low cholesterol levels and low activity or inhibition of that pathway occurs when cholesterol levels are normal or elevated, respectively. However, what is not known is if SREBP‐2 can be activated by changes in FPP levels when cholesterol levels are unaltered as in the case of AD. To begin to understand FPP and GGPP regulation in brain, effects of inhibition of FPP synthase by a direct inhibitor and inhibition of HMG‐CoA reductase by a statin on translocation of SREBP‐2 into the nucleus were examined in mouse primary neurons and SH‐SY5Y neuroblastoma cells. Cells were treated with simvastatin or alendronate for 48 h and protein levels determined by Western analysis. Simvastatin‐induced inhibition of HMG‐CoA reductase significantly increased SREBP‐2 abundance in the nuclear fraction of cells. In contrast, inhibition of FPP synthase which reduces FPP levels but not cholesterol did not stimulate movement of SREBP‐2 into the nucleus. SREBP‐2 activation may not be driving the increase in FPP levels in AD brain. A consequence of the increase in FPP and GGPP in AD patients could be an over‐abundance of prenylated proteins which could certainly exacerbate cell dysfunction. Supported by grants from the National Institutes of Health AG‐23524, AG‐18357 and the Department of Veterans Affairs.