Alzheimer's disease (AD) has been associated with magnesium ion (Mg2+) deficits and interleukin-1 beta (IL-1 beta) elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1 beta expression during Mg (2+) dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1 beta reduction using a recently developed compound, magnesium-L-threonate (MgT). Using human glioblastoma A172 and mouse brain D1A glial cells as an in vitro model system, we delineated the signaling pathways by which MgT suppressed the expression of IL-1 beta in glial cells. In detail, we found that MgT incubation stimulated the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and peroxisome proliferator-activated receptor gamma (PPAR gamma) signaling pathways by phosphorylation, which resulted in IL-1 beta suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPAR gamma induced IL-1 beta upregulation in MgT-stimulated glial cells. In accordance with our in vitro data, the intracerebroventricular (i.c.v) injection of MgT into the ventricles of APP/PS1 transgenic mice and treatment of Ab precursor protein (APP)/PS1 brain slices suppressed the mRNA and protein expression of IL-1 beta. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg (2+) influx into the ventricles of the mice blocked the effects of IL-1 beta or amyloid beta-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1 beta expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation. Cellular & Molecular Immunology (2017) published online 9 November 2015