Research Article Details
| Article ID: | A35934 |
| PMID: | 19387107 |
| Source: | J Alzheimers Dis |
| Title: | Mechanisms of ceramide-mediated neurodegeneration. |
| Abstract: | 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. |
| DOI: | 10.3233/JAD-2009-0983 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| Target ID | Target Name | GENE | Action | Class | UniProtKB ID | Entry Name |
|---|
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |