Magnesium Delays The Pathological Process Of APP/PS1 Transgenic Mice Through Inhibiting The TNF-?-Mediated Inflammatory Response

Alzheimer's disease(AD)is a neurodegenerative disease,which is characterized clinically by cognitive impairment and memory progressive decline.The main pathological features of AD include the formation of senile plaques(SP)induced by A?aggregation between neurons,neurofibrillary tangles(NFTs)in neurons caused by tau phosphorylation,and neuroinflammation mediated by neuroglial cells including astrocytes and microglia.Previous studies have shown that neuroinflammatory mechanisms are critical for the progression of AD.The activated neuroglial cells around the SP could produce and release a large number of inflammatory factors and cytotoxins,resulting in the degeneration or death of acetylcholinesterergic neurons,and development of clinical symptoms such as progressive cognitive impairment.Magnesium ion(Mg2+)is one of the important trace elements in the body which participates in various cell biological functions of the body.Interestingly,brain Mg2+level and serum Mg2+ concentration are significantly lower in patients with AD than that of age-matched normal subjects,suggesting that the dysregulation of Mg2+levels may play an important role in the pathogenesis and progression of AD.However,the underlying mechanism has yet to be defined.It has been reported that Mg2+ could inhibit the expression of Interleukin-1?(IL-1?)in AD model mice,suggesting that Mg2+implicated in reducing neuroinflammation during the course of AD development.The present study focused on the molecular mechanism whether Mg2+ can delay the pathological process of AD by inhibiting the inflammation response in the brain.In addition,the key pathogenic protein A? is generated by ?-and ?-secretase cleavages of amyloid precursor protein(APP).Therefore,in this study,we systematically evaluated whether Mg2+ could inhibit the production and deposition of A? by influencing the activity of APP cleavage enzymes.In the present study,we selected human neuroblastoma SH-SY5Y cells,mouse neuroblastoma N2a cells,human glioblastoma A172 cells,mouse microglia BV2 and astrocytes D1A cells as an in vitro model system,and APPswe/PS1DE9(APP/PS1)transgenic(Tg)mice as AD mouse model.The Mg2+-containing compound,magnesium-L-threonate(MgT),was used as the model drug.Subsequently,molecular biological,morphological and behavioral methods were used to explore the molecular mechanisms of Mg2+ in attenuating the neuropatnological changes and cognitive decline in APP/PS1 Tg mice.The results were as followed:(1)Tumor necrosis factor-?(TNF-?)which upregulated in the brain of AD patients and APP/PS1 Tg mice could accelerate inflammation response through activating the neuroglial cells in the mouse brain;A?oligomers promoted neuroglial cells activation and released TNF-? leading to inflammatory response in AD brain;Mg2+downregulated the mRNA and protein expression of TNF-? through inhibiting the PI3K-AKT/NF-?B signaling pathway,which in turn suppressed the activation of microglia and astrocytes around the A? senile plaque and ultimately inhibited the inflammatory response in the brain of AD mice.(2)TNF-? aggravated the pathogenesis of AD by increasing the expression of y-secretase subunits,Anterior-pharynx-defective protein 1(APH-1),Presenilin enhancer 2(PEN-2),and Nicastrin(NCT),which upregulated in the brain of AD patients and APP/PS1 Tg mice;A? oligomers accelerated pathological changes of AD by increasing the expression ?-secretase subunits;Mg2+ decreased the mRNA and protein expression of APH-1 and PEN-2/NCT through suppressing the ERK1/2/PPAR? and PI3K-AKT/NF-?B signaling pathway,which in turn reduced the A? deposition.(3)Behavioural studies showed that Mg2+ could significantly improve the learning ability and the cognitive decline of APP/PS1 Tg mice.In summary,the present study has demonstrated that Mg2+ treatment decreased the expression levels of TNF-? and ?-secretase subunits,inhibited the inflammatory response in the brain,decreased the production and accumulation of SPs,and ultimately attenuated the cognitive decline of AD model mice.This study provides a full theoretical basis for the establishment of a new strategy for the prevention and treatment of neurodegenerative diseases such as AD,based on regulation of brain Mg2+homeostasis and anti-inflammation.