title: The Role of Oxidized Cholesterol in Diabetes-Induced Lysosomal Dysfunction in the Brain.
abstract: Abnormalities in lysosomal function have been reported in diabetes, aging, and age-related degenerative diseases. These lysosomal abnormalities are an early manifestation of neurodegenerative diseases and often precede the onset of clinical symptoms such as learning and memory deficits; however, the mechanism underlying lysosomal dysfunction is not known. In the current study, we investigated the mechanism underlying lysosomal dysfunction in the cortex and hippocampi, key structures involved in learning and memory, of a type 2 diabetes (T2D) mouse model, the leptin receptor deficient db/db mouse. We demonstrate for the first time that diabetes leads to destabilization of lysosomes as well as alterations in the protein expression, activity, and/or trafficking of two lysosomal enzymes, hexosaminidase A and cathepsin D, in the hippocampus of db/db mice. Pioglitazone, a thiazolidinedione (TZD) commonly used in the treatment of diabetes due to its ability to improve insulin sensitivity and reverse hyperglycemia, was ineffective in reversing the diabetes-induced changes on lysosomal enzymes. Our previous work revealed that pioglitazone does not reverse hypercholesterolemia; thus, we investigated whether cholesterol plays a role in diabetes-induced lysosomal changes. In vitro, cholesterol promoted the destabilization of lysosomes, suggesting that lysosomal-related changes associated with diabetes are due to elevated levels of cholesterol. Since lysosome dysfunction precedes neurodegeneration, cognitive deficits, and Alzheimer's disease neuropathology, our results may provide a potential mechanism that links diabetes with complications of the central nervous system.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA. robinsoc@musc.edu.|Department of Neurosciences, Medical University of South Carolina, Charleston, SC, 29425, USA. robinsoc@musc.edu.|Department of Neurology and Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, 309D2 Clinical Sciences Building, MSC 606, Charleston, SC, 29425, USA. robinsoc@musc.edu.
authors.forename: Catrina
authors.initials: C
authors.lastname: Sims-Robinson
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bakeman
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Rosko
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Glasser
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism; D002540:Cerebral Cortex / Q000201:enzymology / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000201:enzymology / Q000473:pathology*; D005453:Fluorescence; D005947:Glucose / Q000378:metabolism; D054818:Hexosaminidase A / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia / Q000150:complications / Q000473:pathology; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000473:pathology*; D051379:Mice; D010084:Oxidation-Reduction; D010641:Phenotype; D000077205:Pioglitazone; D013194:Staining and Labeling; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D045162:Thiazolidinediones; D002784:Cholesterol; D054818:Hexosaminidase A; D002402:Cathepsin D; D005947:Glucose; D000077205:Pioglitazone
keywords: Brain; Cathepsin D; Central nervous system; Cholesterol; Lysosome; Type 2 diabetes