Calpain Inhibitor Calpeptin Improves Alzheimer’s Disease–Like Cognitive Impairments and Pathologies in a Diabetes Mellitus Rat Model

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.