Abstract
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.
Highlights
Magnesium ions (Mg2+) were recently found to be downregulated in the brain tissue of Alzheimer’s disease (AD) patients compared to those of healthy controls, especially in the hippocampus (Cilliler et al, 2007)
As shown in (Figure 1A), tumor necrosis factor-α (TNF-α) immunostaining was evident in the human cerebral cortex, and the positive staining gradually increased with the progression of AD
In accordance with these data, TNF-α immunostaining was induced in the cerebral cortex and the dentate gyrus (DG) region of the hippocampus in 3-month-old APP/presenilin 1 (PS1) transgenic mice compared with wild-type C57BL/6 mice (WT) C57BL/6 mice (Figure 1B)
Summary
Magnesium ions (Mg2+) were recently found to be downregulated in the brain tissue of Alzheimer’s disease (AD) patients compared to those of healthy controls, especially in the hippocampus (Cilliler et al, 2007). Preclinical studies have shown that MMFS-01, a derivative compound of magnesium-L-threonate (MgT) was effective in alleviating cognitive decline in aging rodents (Liu G. et al, 2015). Mg2+ Inhibits the Activity of TNF-α and γ-Secretase cognitive deficits in AD mouse model (Li et al, 2014). Our prior work revealed that Mg2+ treatment enhanced clearance of Aβ in an APH1α/1β-dependent manner in APP/PS1 transgenic (Tg) mice (Yu et al, 2015). All of this evidence points to the fact that Mg2+ influx is beneficial for treating AD
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