Manganese Induces Tau Hyperphosphorylation through the Activation of ERK MAPK Pathway in PC12 Cells

Abstract

Manganese has long been known to induce neurological degenerative disorders. Emerging evidence indicates that hyperphosphorylated tau is associated with neurodegenerative diseases, but whether such hyperphosphorylation plays a role in manganese-induced neurotoxicity remains unclear. To fill this gap, we investigated the effects of manganese on tau phosphorylation in PC12 cells. In our present research, treatment of cells with manganese increased the phosphorylation of tau at Ser199, Ser202, Ser396, and Ser404 as detected by Western blot. Moreover, this manganese-induced tau phosphorylation paralleled the activation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK). The mitogen-activated protein kinase kinase-1 (MEK1) inhibitor PD98059, which inhibits the activation of ERK MAPK, partially attenuated manganese-induced tau hyperphosphorylation and cytotoxicity. Moreover, the activation of ERK MAPK was involved in the activation of glycogen synthase kinase-3β (GSK-3β) kinase, which also contributed to the hyperphosphorylation of tau and the cytotoxicity in PC12 cells induced by manganese. Taken together, we found for the first time that the exposure to manganese can cause the hyperphosphorylation of tau, which may be connected with the activation of ERK MAPK.

In VitroManganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats

“…Additionally, in the same experimental protocol, Mn impaired motor coordination later at the 3rd, 4th, and 5th week of life. These results were in line with recent evidence indicating that MAPK pathways might be involved in the neurotoxicity induced by Mn in various experimental models, such as mesencephalic cells [16], PC12 cells [15, 23, 35], microglial cells [36, 37], primary astrocyte culture [17], and in vivo developmental exposure [12, 13]. However, the current knowledge on Mn-induced neurotoxicity does not allow for stating whether changes in MAPK signaling pathways represent cause or consequence of Mn-induced cell toxicity.…”

Waterborne manganese exposure alters plasma, brain, and liver metabolites accompanied by changes in stereotypic behaviors

“…Additionally, elevated free cholesterol influences β- and γ-secretase activity enhancing amyloid β production (Shobab et al, 2005). Mn has also been directly linked to tau hyperphosphorylation in PC12 cells (Cai et al, 2011). Changes in lipid availability may also compromise membrane integrity by increasing fatty acid and cholesterol incorporation, thereby altering normal structure and dynamics.…”

Influence of iron metabolism on manganese transport and toxicity

“…Specifically, both iron and Mn can accelerate dopamine auto-oxidation to form cytotoxic quinones and produce ROS 24, 186, 187 . In addition, Mn induces hyperphosphorylation of tau protein 188 , and iron promotes the aggregation of hyperphosphorylated tau protein 189 . It is thus plausible that high levels of both metals could synergistically lead to the accumulation of neurofibrillary tangles, a hall mark of Alzheimer’s diseases.…”