Magnesium-L-threonate treats Alzheimer's disease by modulating the microbiota-gut-brain axis

Disturbances in the microbiota-gut-brain axis may contribute to the development of Alzheimer's disease. Magnesium-L-threonate has recently been found to have protective effects on learning and memory in aged and Alzheimer's disease model mice. However, the effects of magnesium-L-threonate on the gut microbiota in Alzheimer's disease remain unknown. Previously, we reported that magnesium-L-threonate treatment improved cognition and reduced oxidative stress and inflammation in a double-transgenic line of Alzheimer's disease model mice expressing the amyloid-β precursor protein and mutant human presenilin 1(APP/PS1). Here, we performed 16S r RNA amplicon sequencing and liquid chromatography-mass spectrometry to analyze changes in the microbiome and serum metabolome following magnesium-Lthreonate exposure in a similar mouse model. Magnesium-L-threonate modulated the abundance of three genera in the gut microbiota, decreasing Allobaculum and increasing Bifidobacterium and Turicibacter. We also found that differential metabolites in the magnesiumL-threonate-regulated serum were enriched in various pathways associated with neurodegenerative diseases. The western blotting detection on intestinal tight junction proteins(zona occludens 1, occludin, and claudin-5) showed that magnesium-L-threonate repaired the intestinal barrier dysfunction of APP/PS1 mice. These findings suggest that magnesium-L-threonate may reduce the clinical manifestations of Alzheimer's disease through the microbiota-gut-brain axis in model mice, providing an experimental basis for the clinical treatment of Alzheimer's disease.

Chronic Oral Administration of Magnesium-L-Threonate Prevents Oxaliplatin-Induced Memory and Emotional Deficits by Normalization of TNF-a/NF-j B Signaling in Rats

Antineoplastic drugs such as oxaliplatin(OXA)often induce memory and emotional deficits.At present,the mechanisms underlying these side-effects are not fully understood,and no effective treatment is available.Here,we show that the short-term memory deficits and anxietylike and depression-like behaviors induced by intraperitoneal injections of OXA(4 mg/kg per day for 5 consecutive days) were accompanied by synaptic dysfunction and downregulation of the NR2 B subunit of N-methyl-Daspartate receptors in the hippocampus,which is critically involved in memory and emotion.The OXA-induced behavioral and synaptic changes were prevented by chronic oral administration of magnesium-L-threonate(L-TAMS,604 mg/kg per day,from 2 days before until the end of experiments).We found that OXA injections significantly reduced the free Mg~(2+) in serum and cerebrospinal fluid(from ~0.8 mmol/L to ~ 0.6 mmol/L).The Mg~(2+) deficiency(0.6 mmol/L) upregulated tumor necrosis factor(TNF-α) and phospho-p65(p-p65),an active form of nuclear factor-kappaB(NF-κB),and downregulated the NR2 B subunit in cultured hippocampal slices.Oral L-TAMS prevented the OXA-induced upregulation of TNF-α and p-p65,as well as microglial activation in the hippocampus and the medial prefrontal cortex.Finally,similar to oral L-TAMS,intracerebroventricular injection of PDTC,an NF-κB inhibitor,also prevented the OXAinduced memory/emotional deficits and the changes in TNF-α,p-p65,and microglia.Taken together,the activation of TNF-α/NF-κB signaling resulting from reduced brain Mg~(2+) is responsible for the memory/emotional deficits induced by OXA.Chronic oral L-TAMS may be a novel approach to treating chemotherapy-induced memory/emotional deficits.

Magnesium ion influx reduces neuroinflammation in Aβ precursor protein/Presenilin 1 transgenic mice by suppressing the expression of interleukin-1β

Alzheimer＇s disease （AD） has been associated with magnesium ion （Mg2＋） deficits and interleukin-1β（IL-1β） elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1β expression during Mg2＋ dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1β reduction using a recently developed compound, magnesium-L-threonate （MgT）. Using human glioblastoma A172 and mouse brain DIA glial cells as an in vitro model system, we delineated the signaling pathways by which MgT suppressed the expression of IL-1β in glial cells. In detail, we found that MgT incubation stimulated the activity of extracellular signal-regulated protein kinases I and 2 （ERK1/2） and peroxisome proliferator-activated receptor gamma （PPARγ） signaling pathways by phosphorylation, which resulted in IL-1β suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPARγ, induced IL-1β upregulation in MgT-stimulated glial cells. In accordance with our in vitrodata, the intracerebroventricular （i.c.v） injection of MgT into the ventricles of APP/PS1 transgenic mice and treatment of Aβ precursor protein （APP）/PS1 brain slices suppressed the mRNA and protein expression of IL-1β. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg2＋ influx into the ventricles of the mice blocked the effects of IL-1β or amyloid p-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1β expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation.