Abstract
Diabetes-related cognitive impairment has been shown in diverse epidemiological investigations and lab-based studies, although the underlying pathological mechanisms remain unclear. Unbalanced protein homeostasis may contribute to cognitive decline by inducing abnormal protein aggregation in the diabetic brain. This study aimed to determine possible changes in the proteasome, which is an important pathway involved in abnormal protein degradation. To this end, we examined potential alterations of proteasomal subunits and hydrolytic activity in the brain of diabetic rats fed with high-fat diet combined with small doses of streptozotocin (STZ). Furthermore, lactacystin were used to inhibit proteasomal activity in vivo and typical Alzheimer’s disease (AD)-like pathologies were detected, including amyloid-beta, tau phosphorylation, and oxidative protein changes. Our results showed that proteasomal activity increased in the brains of diabetic rats compared to age-matched control rats. After proteasome inhibition, the levels of tau phosphorylation and protein oxidative modification significantly increased; however, no changes were detected in the pathway involved in amyloid production. These results indicated that changes in protein homeostasis balance in diabetes play a role in some typical AD-like changes, especially in oxidative protein degradation, providing evidence that prevention of diabetes-induced protein imbalance may be a potential therapeutic target.
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The datasets generated during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported by the National Natural Science Foundation of China (NSFC) No.81541116 and No.81760236 to ZHAO Bei. Thanks to Dr. KUNDU for his kindly help in English revision during review process.
Funding
This work was supported by the National Natural Science Foundation of China (NSFC) No.81541116 and No.81760236 to ZHAO Bei.
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Gao Han and Zhou Ye, biochemistry experiment and manuscript writing. Jin peng-shuai and Wu Dong-gui, work in diabetic rat model establishment. Wang Yu-na and Zhao Xi, work in data analysis.
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Animal experiment was carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80–23) and the animal experiments procedures involved in this experiment were approved by the animal ethics committee of Dali University.
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Gao, H., Zhou, Y., Jin, Ps. et al. Molecular alteration of the proteasome contributes to AD-like pathology in the brain of HFD-STZ diabetic rats. Metab Brain Dis 38, 1013–1024 (2023). https://doi.org/10.1007/s11011-022-01151-w
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DOI: https://doi.org/10.1007/s11011-022-01151-w