Mechanisms of ceramide-mediated neurodegeneration.
Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be associated with cognitive impairment or early neurodegeneration. Previously, we showed that diet-induced obesity with T2DM and NASH results in mild neurodegeneration with some features of AD, including brain insulin resistance. In a companion study, we correlated obesity/T2DM/NASH-associated central nervous system (CNS) abnormalities with increased pro-ceramide gene expression in liver. Since ceramides are neurotoxic and cause insulin resistance, we directly investigated the role of ceramides as mediators of neurodegeneration using an in vitro culture model. We treated PNET2 human CNS neuronal cells with D-erythro-Ceramide analogs (C2Cer:N-acetylsphinganine and C6Cer:N-hexanoylsphinganine), or the inactive dihydroceramide analog (C2DCer) for 48 h, and probed for changes in genes and proteins that are critical to insulin/IGF signaling, and associated with neurodegeneration. Exposure to C6Cer>C2Cer impaired energy metabolism, viability, and insulin and insulin-like growth factor signaling mechanisms, and resulted in increased levels of AbetaPP-Abeta and pTau, whereas C2D had no significant effect on these parameters. CNS exposure to neurotoxic ceramides from exogenous sources, including liver, can cause neurodegeneration with impairments in insulin and IGF signaling mechanisms, similar to the findings in experimental models of obesity/T2DM, and NASH.
Tong
Ming
M
Department of Medicine, Division of Gastroenterology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI 02903, USA.
de la Monte
Suzanne M
SM
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D002518:Ceramides / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000502:physiology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018242:Neuroectodermal Tumors, Primitive / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism
D002518:Ceramides; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D009419:Nerve Tissue Proteins; D025801:Ubiquitin; D000255:Adenosine Triphosphate; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D002795:Choline O-Acetyltransferase; D011972:Receptor, Insulin; D000110:Acetylcholinesterase