Magnesium Ions Inhibit the Expression of Tumor Necrosis Factor ? and the Activity of ?-Secretase in a ?-Amyloid Protein-Dependent Mechanism in APP/PS1 Transgenic Mice.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative disease characterized by cognitive impairment. The neuropathological features of AD are the aggregation of extracellular amyloid ?-protein (A?) and tau phosphorylation. Recently, AD was found to be associated with magnesium ion (Mg2+) deficit and tumor necrosis factor-alpha (TNF-?) elevation in the serum or brains of AD patients. To study the relationship between Mg2+ and TNF-?, 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-? by restoring the levels of Mg2+ in glial cells. In addition, PI3-K/AKT and NF-?B signals play critical roles in mediating the effects of Mg2+ on suppressing the expression of TNF-?. 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-?B-dependent mechanism. As the major components of ?-secretase, overexpression of presenilin 1 (PS1), PEN2 and NCT potentially promote the synthesis of A?, which in turn activates TNF-? in glial cells. Reciprocally, TNF-? stimulates the expression of PEN2 and NCT in neurons. The crosstalk between TNF-? and A? in glial cells and neurons could ultimately aggravate the development and progression of AD.

SUBMITTER: Yu X 

PROVIDER: S-EPMC5988891 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature