期刊
MOLECULAR NEUROBIOLOGY
卷 53, 期 4, 页码 2287-2296出版社
HUMANA PRESS INC
DOI: 10.1007/s12035-015-9207-1
关键词
Type 2 diabetes; Brain; Lysosome; Cathepsin D; Cholesterol; Central nervous system
资金
- National Institutes of Health (NIA Training Grant) [T32 AG000114]
- A. Alfred Taubman Medical Research Institute
- Program for Neurology Research and Discovery
- NIDDK [DK020572]
- National Institutes of Health (NINDS Neurology Training Grant) [T32 NS007222]
- National Institutes of Health (Animal Models of Diabetic Complications Consortium) [NIH U01-DK076160]
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.
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