PMID- 19387107
OWN - NLM
STAT- MEDLINE
DCOM- 20090707
LR  - 20220223
IS  - 1387-2877 (Print)
IS  - 1875-8908 (Electronic)
IS  - 1387-2877 (Linking)
VI  - 16
IP  - 4
DP  - 2009
TI  - Mechanisms of ceramide-mediated neurodegeneration.
PG  - 705-14
LID - 10.3233/JAD-2009-0983 [doi]
AB  - 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.
FAU - Tong, Ming
AU  - Tong M
AD  - 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.
FAU - de la Monte, Suzanne M
AU  - de la Monte SM
LA  - eng
GR  - AA02666/AA/NIAAA NIH HHS/United States
GR  - R37 AA011431/AA/NIAAA NIH HHS/United States
GR  - AA12908/AA/NIAAA NIH HHS/United States
GR  - AA16126/AA/NIAAA NIH HHS/United States
GR  - R01 AA012908/AA/NIAAA NIH HHS/United States
GR  - R56 AA011431/AA/NIAAA NIH HHS/United States
GR  - AA11431/AA/NIAAA NIH HHS/United States
GR  - AA02169/AA/NIAAA NIH HHS/United States
GR  - R01 AA011431/AA/NIAAA NIH HHS/United States
GR  - R37 AA002666/AA/NIAAA NIH HHS/United States
GR  - K24 AA016126/AA/NIAAA NIH HHS/United States
GR  - R01 AA002666/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - Netherlands
TA  - J Alzheimers Dis
JT  - Journal of Alzheimer's disease : JAD
JID - 9814863
RN  - 0 (Ceramides)
RN  - 0 (IRS1 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Ubiquitin)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 1.2.1.- (Glyceraldehyde-3-Phosphate Dehydrogenases)
RN  - EC 2.3.1.6 (Choline O-Acetyltransferase)
RN  - EC 2.7.10.1 (Receptor, Insulin)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
SB  - IM
MH  - Acetylcholinesterase/genetics/metabolism
MH  - Adenosine Triphosphate/metabolism
MH  - Cell Line, Tumor
MH  - Cell Size/drug effects
MH  - Ceramides/*pharmacology
MH  - Choline O-Acetyltransferase/genetics/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Energy Metabolism/drug effects
MH  - Gene Expression Regulation, Neoplastic/*drug effects/physiology
MH  - Glyceraldehyde-3-Phosphate Dehydrogenases/genetics/metabolism
MH  - Humans
MH  - Insulin/genetics/metabolism
MH  - Insulin Receptor Substrate Proteins/genetics/metabolism
MH  - Nerve Degeneration/*metabolism
MH  - Nerve Tissue Proteins/genetics/metabolism
MH  - Neuroectodermal Tumors, Primitive/metabolism
MH  - Receptor, Insulin/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Ubiquitin/genetics/metabolism
PMC - PMC4550322
MID - NIHMS716287
EDAT- 2009/04/24 09:00
MHDA- 2009/07/08 09:00
PMCR- 2015/08/26
CRDT- 2009/04/24 09:00
PHST- 2009/04/24 09:00 [entrez]
PHST- 2009/04/24 09:00 [pubmed]
PHST- 2009/07/08 09:00 [medline]
PHST- 2015/08/26 00:00 [pmc-release]
AID - 7G72R6J084050LX4 [pii]
AID - 10.3233/JAD-2009-0983 [doi]
PST - ppublish
SO  - J Alzheimers Dis. 2009;16(4):705-14. doi: 10.3233/JAD-2009-0983.