Abstract
Diabetes mellitus (DM) has been considered an accelerator of Alzheimer’s disease (AD), but the cellular and molecular mechanisms underlying this effect are not fully understood. Here, we attempted to determine the role and regulatory mechanism of calpain in the AD-like cognitive decline and pathological changes in rats caused by DM. In the initial stages, our results verified that DM model rats showed cognitive impairment, as well as a loss of neurons, decreased pericyte marker (PDGFR-β and α-SMA), and calpain-2 expression and amyloid-β (Aβ) deposition in the hippocampal tissues. In high glucose–induced primary pericytes, the cell apoptotic rate was increased, and cell proliferation was inhibited in a time-dependent manner. The protein level of calpain-2 was also upregulated by HG induction, but the level of calpain-1 did not change with HG treatment, which was also observed in DM model rats. Subsequently, some DM model rats were administered calpeptin, an inhibitor of calpain. Our data revealed that calpeptin treatment significantly suppressed calpain-1 and calpain-2 expression in the hippocampal tissues and effectively improved the cognitive impairments of DM model rats. Neuronal loss, Aβ accumulation, pericyte loss, inflammation, and oxidative stress injury in the hippocampal tissues of DM model rats were also partly rescued by calpeptin administration. Our work demonstrated that the calpain inhibitor calpeptin could alleviate DM-induced AD-like cognitive impairments and pathological changes in rats, and this effect may be associated with pericytes. Calpeptin may become a promising drug to treat the AD-like complications of DM.
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The data used and/or analysed during the current study are available from the corresponding author on reasonable request.
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This study was supported by the National Natural Science Foundation of China (Grant No. 82060214).
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ML, SQZ, and ZYT designed the study. GGW, LYQ, SQY, TPL, XP, and XL carried out the experiments, and GGW and LYQ analyzed the data. ML and SQZ drafted the manuscript. All authors critically read and revised the manuscript and approved the final version of the manuscript for submission.
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Supplementary Figure 1.
Examination of cognitive function in rats. A DM rat model was constructed by injecting STZ in combination with a HFHS diet. (A) The levels of blood glucose in rats under fasting conditions were detected. (B) The action routes of rats in the MWM test. (C) The time that rats spent at the aim quadrant was recorded. (D) The frequency with which rats passed the safe platform was recorded. (E) The mean swimming speed of rats in the test was recorded. **P < 0.01 compared with the normal group. (TIF 1595 kb)
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Li, M., Zhou, S., Wang, G. et al. Calpain Inhibitor Calpeptin Improves Alzheimer’s Disease–Like Cognitive Impairments and Pathologies in a Diabetes Mellitus Rat Model. Neurotox Res 40, 1248–1260 (2022). https://doi.org/10.1007/s12640-022-00561-z
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DOI: https://doi.org/10.1007/s12640-022-00561-z