Abstract
Alzheimer's disease (AD) is the most common type of dementia, and the abnormal hyperphosphorylation of the tau protein is the main component of its pathogenesis. Calpain was found to be abnormally activated in neurofibrillary tangles (NFTs) in a previous report. Cornel iridoid glycosides (CIG) have been reported to reduce the hyperphosphorylation of tau protein. Nevertheless, the role of calpain in the reduction tau hyperphosphorylation by CIG remains unclear. In the present study, we investigated the effect of CIG on calpain activity through in vitro and in vivo experiments. Western blotting results suggested that CIG decreased the phosphorylation of tau at Ser 404 and Ser 262 sites in P301S mice. Moreover, CIG inhibited the activity of calpain and glycogen synthase kinase 3β (GSK-3β) and enhanced the activity of protein phosphatase 2A (PP2A) both in vivo and in vitro. CIG also inhibited the activation of PP2A and reduced the GSK-3β activity caused by the calpain activator dibucaine. In addition, the main components of CIG, morroniside and loganin, play an equivalent role in reducing calpain activity, as the effect of their combined use is equivalent to that of CIG. The abovementioned findings revealed that CIG improved PP2A activity and reduced GSK-3β activity by adjusting the activity of calpain 1, leading to a reduction in the phosphorylation of tau. This study highlights the remarkable therapeutic potential of CIG for managing AD.
Highlights
Reports analyzing stained brain tissue from Alzheimer’s disease (AD) patients found that neurons containing neurofibrillary tangles (NFTs) showed high expression levels of the protein calpain [3]. e calpain family has 15 members; calpain 1 plays an important role in the activation of glycogen synthase kinase 3β (GSK-3β) and protein phosphatase 2A (PP2A) [4,5,6], and calpain 2 can regulate the activity of PP2A [7]
We further examined the level of tau phosphorylation in the seven groups: nTg, nTg treated with Cornel iridoid glycoside (CIG) (100 mg/kg), P301S mice, low-dose CIG (50 mg/kg)-treated P301S mice, middle-dose CIG (100 mg/kg)-treated P301S mice, high-dose CIG (200 mg/ kg)-treated P301S mice, and MEM-treated P301S mice
Inhibitors of calpain diminish the hyperphosphorylation of tau [19]. is experiment showed that CIG and its active ingredients morroniside and loganin could reduce tau hyperphosphorylation by regulating the activity of calpain
Summary
Reports analyzing stained brain tissue from Alzheimer’s disease (AD) patients found that neurons containing NFTs showed high expression levels of the protein calpain [3]. e calpain family has 15 members; calpain 1 plays an important role in the activation of glycogen synthase kinase 3β (GSK-3β) and protein phosphatase 2A (PP2A) [4,5,6], and calpain 2 can regulate the activity of PP2A [7]. Cornel iridoid glycoside (CIG) was found in the literature to significantly inhibit abnormal hyperphosphorylation of tau protein, protect the structure of neuronal microtubules, reduce the formation of neurofibrillary tangles, and increase the number of surviving neurons in the cerebral cortex and hippocampus and was shown to remarkably improve the learning and memory function in AD animal models [14]. Based on these reports and our preliminary data, we examined whether CIG oral treatment can revert the hyperphosphorylation of tau protein and improve cognitive functions in AD mouse models by inhibiting calpain activity
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