withaferin-a and 24-hydroxycholesterol

Keeping in view the fact that the most pathognomonic feature of Alzheimer's disease is the abnormal processing of neuronal cell membrane amyloid precursor protein accompanied by significantly elevated human serum and CSF levels of 24-hydroxycholesterol recognised widely as the specific endogenous ligand of Liver X receptor (LXR-α), the present study was addressed to explore the epigenomic-pathway (if any) that connects LXR-α activation with the genes recognised to be involved in the regulation of aberrant Abeta production leading to the generation of toxic and inflammatory mediators responsible for neuronal death. The results of such a study revealed that LXR-α activation by its specific endogenous or exogenous ligands within neuroblastoma cells resulted in the over-expression of PAR-4 gene accompanied by suppression of AATF gene through its inherent capacity to regulate genes coding for SREBP and NF-κB. Over-expression of PAR-4 gene was accompanied by aberrant Abeta production followed by ROS generation and subsequent death of neuroblastoma cells used in the present study as a cellular model for neurons. Further based upon these results, it was proposed that Abeta-induced heme oxygenase-1 can ensure cholesterol-oxidation to provide endogenous ligands for the sustained activation of neuronal LXR-α dependent epigenomic-pathway leading to neuronal death observed in Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Apoptosis; Apoptosis Regulatory Proteins; Cloning, Molecular; Epigenomics; Gene Expression Regulation; Humans; Hydroxycholesterols; Liver X Receptors; Neuroblastoma; Neurons; Orphan Nuclear Receptors; Reactive Oxygen Species; Recombinant Proteins; Repressor Proteins; Tumor Cells, Cultured; Withanolides