Magnesium-L-threonate exhibited a neuroprotective effect against oxidative stress damage in HT22 cells and Alzheimer’s disease mouse model

BACKGROUND Oxidative stress results in the production of excess reactive oxygen species(ROS)and triggers hippocampal neuronal damage as well as occupies a key role in the pathological mechanisms of neurodegenerative disorders such as Alzheimer’s disease(AD).A recent study confirmed that magnesium had an inhibitory effect against oxidative stress-related malondialdehyde in vitro.However,whether Magnesium-L-threonate(MgT)is capable of suppressing oxidative stress damage in amyloidβ(Aβ)_(25-35)-treated HT22 cells and the AD mouse model still remains to be investigated.AIM To explore the neuroprotective effect of MgT against oxidative stress injury in vitro and in vivo,and investigate the mechanism.METHODS Aβ_(25-35)-induced HT22 cells were preconditioned with MgT for 12 h.APPswe/PS1dE9(APP/PS1)mice were orally administered with MgT daily for 3 mo.After MgT treatment,the viability of Aβ_(25-35)-treated HT22 cells was determined via conducting cell counting kit-8 test and the cognition of APP/PS1 mice was measured through the Morris Water Maze.Flow cytometry experiments were applied to assess the ROS levels of HT22 cells and measure the apoptosis rate of HT22 cells or hippocampal neurons.Expression of B-cell lymphoma 2(Bcl-2),Bcl-2-associated X(Bax),hypoxiainducible factor(HIF)-1α,NADPH oxidase(NOX)4,Aβ_(1-42) and phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt)pathway proteins was quantified by Western blot.RESULTS In vitro data confirmed that Aβ_(25-35)-induced HT22 cells had a significantly lower cell viability,higher ROS level and higher apoptosis rates compared with those of control cells(all P<0.001).MgT prevented the Aβ_(25-35)-triggered oxidative stress damage by elevating viability and decreasing ROS formation and apoptosis of HT22 cells(all P<0.001).APP/PS1 mice exhibited worse cognitive performance and higher apoptosis rate of hippocampal neurons than wild-type(WT)mice(all P<0.01).Meanwhile,significant higher expression of Aβ_(1-42) and NOX4 proteins was detected in APP/PS1 mice than those of WT mice(both P<0.01).MgT also ameliorated the cognitive deficit,suppressed the apoptosis of hippocampal neuron and downregulated the expression of Aβ_(1-42) and NOX4 proteins in APP/PS1 mouse(all P<0.05).Moreover,MgT intervention significantly downregulated HIF-1αand Bax,upregulated Bcl-2 and activated the PI3K/Akt pathway both in vitro and in vivo(all P<0.05).CONCLUSION MgT exhibits neuroprotective effects against oxidative stress and hippocampal neuronal apoptosis in Aβ_(25-35)-treated HT22 cells and APP/PS1 mice.