Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive impairment. The neuropathological features of AD are the aggregation of extracellular amyloid β-protein (Aβ) and tau phosphorylation. Recently, AD was found to be associated with magnesium ion (Mg2+) deficit and tumor necrosis factor-alpha (TNF-α) elevation in the serum or brains of AD patients. To study the relationship between Mg2+ and TNF-α, we used human-or mouse-derived glial and neuronal cell lines or APP/PS1 transgenic (Tg) mice as in vitro and in vivo experimental models, respectively. Our data demonstrates that magnesium-L-threonate (MgT) can decrease the expression of TNF-α by restoring the levels of Mg2+ in glial cells. In addition, PI3-K/AKT and NF-κB signals play critical roles in mediating the effects of Mg2+ on suppressing the expression of TNF-α. In neurons, Mg2+ elevation showed similar suppressive effects on the expression of presenilin enhancer 2 (PEN2) and nicastrin (NCT) through a PI3-K/AKT and NF-κB-dependent mechanism. As the major components of γ-secretase, overexpression of presenilin 1 (PS1), PEN2 and NCT potentially promote the synthesis of Aβ, which in turn activates TNF-α in glial cells. Reciprocally, TNF-α stimulates the expression of PEN2 and NCT in neurons. The crosstalk between TNF-α and Aβ in glial cells and neurons could ultimately aggravate the development and progression of AD.
Yu, X., Guan, P. P., Zhu, D., Liang, Y. Y., Wang, T., Wang, Z. Y., & Wang, P. (2018). Magnesium ions inhibit the expression of tumor necrosis factor α and the activity of γ-secretase in a β-amyloid protein-dependent mechanism in APP/PS1 transgenic mice. Frontiers in Molecular Neuroscience, 11. https://doi.org/10.3389/fnmol.2018.00172