Neuronal apoptosis mediated by inhibition of intracellular cholesterol transport: microarray and proteomics analyses in cultured murine cortical neurons.
Studies suggest that cholesterol imbalance in the brain might be related to the development of neurological disorders. U18666A is a well-known amphiphile which inhibits intracellular cholesterol transport in treated cells. We have previously shown that U18666A leads to apoptosis and cholesterol accumulation in primary cortical neurons, which is associated with activation of caspases and calpains, hyperphosphorylation of tau, and increased oxidative stress markers. However, the mechanisms involved in U18666A-mediated apoptosis remain unknown. In this report, we sought to gain an insight into the molecular processes contributing to the neuronal apoptosis induced by U18666A. The microarray approach was used in conjunction with proteomics techniques to identify specific proteins which may serve as signature biomarkers during U18666A treatment. Eleven differentially expressed proteins were correlated at the gene expression level in a time-dependent manner. These proteins have been shown to play a role in lipid metabolism and transport, responses to cell death, protein folding and trafficking, and regulation of transcription. The identification of these differentially expressed proteins might provide a clue to decipher the intracellular biochemical changes during U18666A-mediated neuronal apoptosis. Our results provide, for the first time, a combined microarray and proteomics analysis of neuronal apoptosis mediated by inhibition of intracellular cholesterol transport. This new insight may greatly facilitate the study of neurodegenerative diseases.
Koh
Chor Hui Vivien
CH
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Peng
Zhao Feng
ZF
Ou
Keli
K
Melendez
Alirio
A
Manikandan
Jayapal
J
Qi
Robert Z
RZ
Cheung
Nam Sang
NS
D000736:Androstenes / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D016000:Cluster Analysis; D015180:Electrophoresis, Gel, Two-Dimensional; D020869:Gene Expression Profiling; D023281:Genomics; D013058:Mass Spectrometry; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification; D040901:Proteomics
D000736:Androstenes; D011506:Proteins; C006261:3-beta-(2-(diethylamino)ethoxy)androst-5-en-17-one; D002784:Cholesterol