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. 2025 Apr 30;34(2):53-62.
doi: 10.5607/en24030. Epub 2025 Apr 16.

Magnesium-L-threonate Ameliorates Cognitive Deficit by Attenuating Adult Hippocampal Neurogenesis Impairment in a Mouse Model of Alzheimer's Disease

Ying Xiong  1 , Yuwen Yang  1 , Yuting Ruan  2 , Wencai Ou  1 , Zhiwen Hu  1 , Wei Li  3 , Nina Xiao  1 , Wang Liao  4 , Jianhua Liu  1 , Zhenlu Liu  1 , Qiong Luo  1 , Feifei Liu  5 , Jun Liu  4
Affiliations

Magnesium-L-threonate Ameliorates Cognitive Deficit by Attenuating Adult Hippocampal Neurogenesis Impairment in a Mouse Model of Alzheimer's Disease

Ying Xiong et al. Exp Neurobiol. .

Abstract

Impaired adult hippocampal neurogenesis is a key pathological mechanism contributing to memory deficits in Alzheimer's disease (AD). Recent studies have shown that elevating magnesium levels promotes neurogenesis by enhancing the neuronal differentiation of adult neural progenitor cells in vitro. Therefore, this in vivo study aims to determine if magnesium-L-threonate (MgT) can ameliorate cognitive deficit of AD mice by attenuating adult hippocampal neurogenesis impairment and to reveal the underlying mechanisms. APPswe/PS1dE9 mice were treated with different doses of MgT and ERK inhibitor PD0325901. The memory ability of each mouse was recorded by Morris Water Maze test. After cognitive test, hippocampus tissues were collected to measure the proportion of BrdU/doublecortin double-labeled cells using the flow cytometry test and assess the expression of doublecortin using PCR and Western blot. Furthermore, the activations of CREB, ERK, P38 and JNK were measured by Western blot to identify the involved mechanisms. The cognitive test confirmed that MgT treatment attenuated the memory impairment of APPswe/PS1dE9 mice. Flow cytometry test showed that Brdu/doublecortin labeled newborn neurons gradually increased following MgT administration. In line with the flow cytometry results, Western blot and PCR confirmed that MgT administration significantly increased doublecortin expression levels. Furthermore, the ratios of p-ERK/ERK and p-CREB/CREB increased with MgT elevation. In addition, these effects of MgT treatment were markedly reversed by PD0325901 supplementation. In conclusion, MgT treatment improved cognitive decline by ameliorating adult hippocampal neurogenesis impairment in this AD model, possibly via ERK/CREB activation.

Keywords: Alzheimer’s disease; Cognitive decline; Magnesium; Neurogenesis.

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Figures

Fig. 1
Fig. 1
MgT treatments ameliorated the cognitive decline of AD mouse. (A) The escape latency of each group. (B) Representative swimming route explored the removed platform of each group. (C) The numbers of platform crossings of each group. (D) The percentage of target quadrant exploration time of each group. (E) The time arrived at the removed platform of each group. (F) The average swimming speed of each group. MgT, magnesium-L-threonate; WT, wild type; TG, transgenic control; LM, low-dose MgT; HM, high-dose MgT; MHP, high-dose MgT+high-dose PD0325901. Data were given as mean±SEM (n=three per group). Ns represented no statistical difference. *p<0.05, **p<0.01, ***p<0.001 versus TG group; #p<0.05, ##p<0.01, ###p<0.001 versus former group.
Fig. 2
Fig. 2
MgT facilitated the DCX expression and hippocampal newborn neurons generation of AD mouse. (A, B) The DCX protein expression of each group. (C) The DCX mRNA expression of each group. (D, E) The percentage of BrdU+/DCX+ cells of each group. DCX, doublecortin; MgT, magnesium-L-threonate; WT, wild type; TG, transgenic control; LM, low-dose MgT; HM, high-dose MgT; MHP, high-dose MgT+high-dose PD0325901. Data were given as mean±SEM (n=three per group). Ns represented no statistical difference. *p<0.05, **p<0.01, ***p<0.001 versus TG group; #p<0.05, ##p<0.01, ###p<0.001 versus former group.
Fig. 3
Fig. 3
MgT treatment promoted the activations of ERK and CREB while didn’t exhibit effects on the activations of P38 and JNK. (A) Western blot data of p-ERK, ERK, p-CREB, CREB, p-JNK, JNK, p-P38 and P38 of each group. (B) The p-ERK/ERK ratio of each group. (C) The p-CREB/CREB ratio of each group. (D) The p-JNK/JNK ratio of each group. (E) The p-P38/P38 ratio of each group. MgT, magnesium-L-threonate; WT, wild type; TG, transgenic control; LM, low-dose MgT; HM, high-dose MgT; MHP, high-dose MgT+high-dose PD0325901. Data were given as mean±SEM (n=three per group). Ns represented no statistical difference. *p<0.05, **p<0.01, ***p<0.001 versus TG group; #p<0.05, ##p<0.01, ###p<0.001 versus former group.
Fig. 4
Fig. 4
PD0325901 treatment reversed the activations of both ERK and CREB induced by MgT administration. (A) Western blot data of p-ERK, ERK, p-CREB and CREB of each group. (B) The p-ERK/ERK ratio of each group. (C) The p-CREB/CREB ratio of each group. MgT, magnesium-L-threonate; HM, high-dose MgT; MLP, high-dose MgT + low-dose PD0325901; MHP, high-dose MgT+high-dose PD0325901. Data were given as mean±SEM (n=three per group). *p<0.05, **p<0.01, ***p<0.001 versus HM group; #p<0.05, ##p<0.01, ###p<0.001 versus former group.
Fig. 5
Fig. 5
PD0325901 treatment reversed the effects of MgT on DCX expression and hippocampal newborn neuron generation of AD mouse. (A, B) The DCX protein expression of each group. (C) The DCX mRNA expression of each group. (D, E) The percentage of BrdU+/DCX+ cells of each group. DCX, doublecortin; MgT, magnesium-L-threonate; HM, high-dose MgT; MLP, high-dose MgT+low-dose PD0325901; MHP, high-dose MgT+high-dose PD0325901. Data were given as mean±SEM (n=three per group). *p<0.05, **p<0.01, ***p<0.001 versus HM group; #p<0.05, ##p<0.01, ###p<0.001 versus former group.
Fig. 6
Fig. 6
PD0325901 treatment reversed the effect of MgT on cognitive deficit of AD mouse. (A) The escape latency of each group. (B) Representative swimming route explored the removed platform of each group. (C) The numbers of platform crossings of each group. (D) The percentage of target quadrant exploration time of each group. (E) The time arrived at the removed platform of each group. (F) The average swimming speed of each group. MgT, magnesium-L-threonate; HM, high-dose MgT; MLP, high-dose MgT+low-dose PD0325901; MHP, high-dose MgT+high-dose PD0325901. Data were given as mean±SEM (n=three per group). Ns represented no statistical difference. *p<0.05, **p<0.01, ***p<0.001 versus HM group; #p<0.05, ##p<0.01, ###p<0.001 versus former group.
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