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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

AO staining in CN treated with glucose. a–c Representative images of control CN and d–f and CN treated with 25 mM glucose for 72 h. Nuclei are stained; green and red puncta represent lysosomes (white arrows). Scale bar represents 25 μm
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Fig4: AO staining in CN treated with glucose. a–c Representative images of control CN and d–f and CN treated with 25 mM glucose for 72 h. Nuclei are stained; green and red puncta represent lysosomes (white arrows). Scale bar represents 25 μm

Mentions: To determine a potential mechanism underlying the lysosomal destabilization and leakage associated with T2D, AO staining was used on live primary CN cultures in the presence or absence of 25 mM glucose treatment. An increase in the green cytosolic fluorescence and/or a decrease in red punctate lysosomes are indicative of a loss of membrane integrity. Microscopy of live cells revealed that 25 mM of glucose treatment for 72 h led to the loss of red lysosomal staining (Fig. 4).Fig. 4


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)

AO staining in CN treated with glucose. a–c Representative images of control CN and d–f and CN treated with 25 mM glucose for 72 h. Nuclei are stained; green and red puncta represent lysosomes (white arrows). Scale bar represents 25 μm
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4644712&req=5

Fig4: AO staining in CN treated with glucose. a–c Representative images of control CN and d–f and CN treated with 25 mM glucose for 72 h. Nuclei are stained; green and red puncta represent lysosomes (white arrows). Scale bar represents 25 μm
Mentions: To determine a potential mechanism underlying the lysosomal destabilization and leakage associated with T2D, AO staining was used on live primary CN cultures in the presence or absence of 25 mM glucose treatment. An increase in the green cytosolic fluorescence and/or a decrease in red punctate lysosomes are indicative of a loss of membrane integrity. Microscopy of live cells revealed that 25 mM of glucose treatment for 72 h led to the loss of red lysosomal staining (Fig. 4).Fig. 4

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