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The Role of Oxidized Cholesterol in Diabetes-Induced Lysosomal Dysfunction in the Brain.

Sims-Robinson C, Bakeman A, Rosko A, Glasser R, Feldman EL - Mol. Neurobiol. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA. robinsoc@musc.edu.

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.

No MeSH data available.


Related in: MedlinePlus

Protein expression and activity of the lysosomal enzyme hexosaminidase A in the brain of T2D mice. a, b Protein expression and c, d activity of hexosaminidase A in the cortex (a, c) and hippocampus (b, d) of db+ and db/db mice at 8 and 20 weeks of age. Actin was used as the loading control (*p < 0.05 and **p < 0.01 compared with db+; n ≥ 6). Activity is expressed in relative fluorescence units (RFU)
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Fig1: Protein expression and activity of the lysosomal enzyme hexosaminidase A in the brain of T2D mice. a, b Protein expression and c, d activity of hexosaminidase A in the cortex (a, c) and hippocampus (b, d) of db+ and db/db mice at 8 and 20 weeks of age. Actin was used as the loading control (*p < 0.05 and **p < 0.01 compared with db+; n ≥ 6). Activity is expressed in relative fluorescence units (RFU)

Mentions: We evaluated the lysosomal enzyme β-hexosaminidase A to examine lysosomal function in T2D. While hexosaminidase A protein expression did not change in the cortex, it was significantly increased in the hippocampus by 33 % at 8 weeks and 28 % at 20 weeks in T2D compared to the nondiabetic control (Fig. 1a, b). Likewise, the activity of hexosaminidase A did not change in the cortex; however, it decreased by 10 % in the hippocampus of T2D mice at 8 weeks of age and increased by 8 % in the hippocampus of T2D mice at 20 weeks of age compared to the nondiabetic control (Fig. 1c, d).Fig. 1


The Role of Oxidized Cholesterol in Diabetes-Induced Lysosomal Dysfunction in the Brain.

Sims-Robinson C, Bakeman A, Rosko A, Glasser R, Feldman EL - Mol. Neurobiol. (2015)

Protein expression and activity of the lysosomal enzyme hexosaminidase A in the brain of T2D mice. a, b Protein expression and c, d activity of hexosaminidase A in the cortex (a, c) and hippocampus (b, d) of db+ and db/db mice at 8 and 20 weeks of age. Actin was used as the loading control (*p < 0.05 and **p < 0.01 compared with db+; n ≥ 6). Activity is expressed in relative fluorescence units (RFU)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4644712&req=5

Fig1: Protein expression and activity of the lysosomal enzyme hexosaminidase A in the brain of T2D mice. a, b Protein expression and c, d activity of hexosaminidase A in the cortex (a, c) and hippocampus (b, d) of db+ and db/db mice at 8 and 20 weeks of age. Actin was used as the loading control (*p < 0.05 and **p < 0.01 compared with db+; n ≥ 6). Activity is expressed in relative fluorescence units (RFU)
Mentions: We evaluated the lysosomal enzyme β-hexosaminidase A to examine lysosomal function in T2D. While hexosaminidase A protein expression did not change in the cortex, it was significantly increased in the hippocampus by 33 % at 8 weeks and 28 % at 20 weeks in T2D compared to the nondiabetic control (Fig. 1a, b). Likewise, the activity of hexosaminidase A did not change in the cortex; however, it decreased by 10 % in the hippocampus of T2D mice at 8 weeks of age and increased by 8 % in the hippocampus of T2D mice at 20 weeks of age compared to the nondiabetic control (Fig. 1c, d).Fig. 1

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, 48109, USA. robinsoc@musc.edu.

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.

No MeSH data available.


Related in: MedlinePlus