Metabolic derangements mediate cognitive impairment and Alzheimer's disease: role of peripheral insulin-resistance diseases.
Herein, we review evidence that systemic insulin-resistance diseases linked to obesity, type 2 diabetes, and non-alcoholic steatohepatitis promote neurodegeneration. Insulin-resistance dysregulates lipid metabolism, which promotes ceramide accumulation with attendant inflammation and endoplasmic reticulum (ER) stress. Mechanistically, we propose that toxic ceramides generated in extra-CNS tissues, e.g. liver, get released into peripheral blood, and subsequently transit across the blood-brain barrier into the brain where they induce brain insulin-resistance, inflammation, and cell death (extrinsic pathway). These abnormalities establish or help propagate a cascade of neurodegeneration associated with increased ER stress and ceramide generation, which exacerbate brain insulin-resistance, cell death, myelin degeneration, and neuro-inflammation. The data suggest that a mal-signaling network mediated by toxic ceramides, ER stress, and insulin-resistance should be targeted to disrupt positive feedback loops that drive the AD neurodegeneration cascade.
Department of Neuropathology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA. Suzanne_DeLaMonte_MD@Brown.edu
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D000544:Alzheimer Disease / Q000150:complications / Q000628:therapy*; D001812:Blood-Brain Barrier; D001921:Brain / Q000473:pathology; D002490:Central Nervous System / Q000473:pathology; D002518:Ceramides / Q000737:chemistry / Q000378:metabolism; D003072:Cognition Disorders / Q000150:complications / Q000473:pathology / Q000628:therapy*; D003920:Diabetes Mellitus / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000473:pathology; D009765:Obesity
D002518:Ceramides