Issue title: Oxidative Stress, Reactive Metabolites, Inflammation, and RAGE – Building a Bridge from Alzheimer's Disease to Diabetes and Vice Versa
Guest editors: Angelika Bierhaus
Article type: Research Article
Authors: Lyn-Cook Jr., Lascelles E.; 1 | Lawton, Margot; 1 | Tong, Ming | Silbermann, Elizabeth | Longato, Lisa | Jiao, Ping | Mark, Princess | Wands, Jack R. | Xu, Haiyan | de la Monte, Suzanne M.; *
Affiliations: Departments of Medicine, Pathology, and Clinical Neuroscience, Divisions of Gastroenterology and Endocrinology, and the Liver Research Center, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA
Correspondence:
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Corresponding author: Dr. Suzanne M. de la Monte, Rhode Island Hospital, 55 Claverick Street, 4th Floor, Providence, RI 02903, USA. Tel.: +1 401 444 7364; Fax: +1 401 444 2939; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: Obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic steatohepatitis (NASH) can be complicated by cognitive impairment and neurodegeneration. Experimentally, high fat diet (HFD)-induced obesity with T2DM causes mild neurodegeneration with brain insulin resistance. Since ceramides are neurotoxic, cause insulin resistance, and are increased in T2DM, we investigated the potential role of ceramides as mediators of neurodegeneration in the HFD obesity/T2DM model. We pair-fed C57BL/6 mice with a HFD or control diet for 4–20 weeks and examined pro-ceramide gene expression in liver and brain and neurodegeneration in the temporal lobe. HFD feeding gradually increased body weight, but after 16 weeks, liver weight surged (P < 0.001) due to lipid (triglyceride) accumulation (P < 0.001), and brain weight declined (P < 0.0001-Trend analysis). HFD feeding increased ceramide synthase, serine palmitoyl transferase, and sphingomyelinase expression in liver (P < 0.05 – P < 0.001), but not brain. In HFD fed mice, temporal lobe levels of ubiquitin (P < 0.001) and 4-hydroxynonenal (P < 0.05 or P < 0.01) increased, and tau, β-actin, and choline acetyltransferase levels decreased (P < 0.05 – P < 0.001) with development of NASH. In obesity, T2DM, or NASH, neurodegeneration with brain insulin resistance may be mediated by excess hepatic production of neurotoxic ceramides that readily cross the blood-brain barrier.
Keywords: Alzheimer's disease, amyloid, diabetes mellitus, high fat diet, insulin resistance, neurodegeneration, non-alcoholic steatohepatitis, obesity
DOI: 10.3233/JAD-2009-0984
Journal: Journal of Alzheimer's Disease, vol. 16, no. 4, pp. 715-729, 2009
