Clioquinol Decreases Levels of Phosphorylated, Truncated, and Oligomerized Tau Protein

Abstract

The neuropathological hallmarks of Alzheimer’s disease (AD) are senile plaques (SPs), which are composed of amyloid β protein (Aβ), and neurofibrillary tangles (NFTs), which consist of highly phosphorylated tau protein. As bio-metal imbalance may be involved in the formation of NFT and SPs, metal regulation may be a direction for AD treatment. Clioquinol (CQ) is a metal-protein attenuating compound with mild chelating effects for Zn2+ and Cu2+, and CQ can not only detach metals from SPs, but also decrease amyloid aggregation in the brain. Previous studies suggested that Cu2+ induces the hyperphosphorylation of tau. However, the effects of CQ on tau were not fully explored. To examine the effects of CQ on tau metabolism, we used a human neuroblastoma cell line, M1C cells, which express wild-type tau protein (4R0N) via tetracycline-off (TetOff) induction. In a morphological study and ATP assay, up to 10 μM CQ had no effect on cell viability; however, 100 μM CQ had cytotoxic effects. CQ decreased accumulation of Cu+ in the M1C cells (39.4% of the control), and both total and phosphorylated tau protein. It also decreased the activity of c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) (37.3% and 60.7% levels of the control, respectively), which are tau kinases. Of note, activation of protein phosphatase 2A (PP2A), which is a tau phosphatase, was also observed after CQ treatment. Fractionation experiments demonstrated a reduction of oligomeric tau in the tris insoluble, sarkosyl soluble fraction by CQ treatment. CQ also decreased caspase-cleaved tau, which accelerated the aggregation of tau protein. CQ activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Although further studies are needed to elucidate the mechanisms responsible for the effects of CQ on tau, CQ may shed light on possible AD therapeutics.

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“…Skin infections can be treated with topical medicines containing clioquinol (148). Furthermore, clioquinol was once widely used as an anti-infective, particularly for diarrhea (149). LY294002 is a highly selective inhibitor of phosphatidylinositol 3 kinase (150,151).…”

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“…It has also been found that clioquinol downregulates β- and γ-secretase and APP expression in the brain ( Wang et al, 2012 ). In vitro experiment demonstrated that clioquinol was able to degrade oligomerized tau and reduce tau tangles ( Lin et al, 2021 ). The effect of clioquinol in AD was also validated in a randomized controlled trial involving patients with moderate-to-severe AD, as oral clioquinol compared to placebo led to slower cognitive decline and reduced CSF Aβ42 ( Ritchie et al, 2003 ).…”

Ketamine Promotes Alzheimer’s-Like Neurodegeneration by Activating Glycogen Synthase Kinase 3 Beta and Inhibiting Protein Phosphatase 2A

“…The activity of GSK-3β was negatively correlated with the phosphorylation degree of enemy Ser9, which means the higher the dephosphorylation degree of Ser9, the higher the level of GSK-3β and the phosphorylation degree of related tau protein will increase [19] . Tau protein phosphorylation is also regulated by PP2A-based protein phosphatase, which inhibits tau protein phosphorylation more strongly than other protein kinases [20,21] . The results indicated that the phosphorylation degree of tau protein at the sites Thr231, S396 and S404 in the observation group was higher than that in the control group, which may be associated with the increase of GSK-3β protein expression and the decrease of PP2A protein expression [22][23][24] .…”