Magnesium boosts the memory restorative effect of environmental enrichment in Alzheimer's disease mice

CNS Neurosci Ther. 2018 Jan;24(1):70-79. doi: 10.1111/cns.12775. Epub 2017 Nov 10.


Background: Environmental enrichment (EE) has been shown to enhance cognitive function in mouse models of Alzheimer's disease (AD). Magnesium-L-threonate (MgT) is a compound with a newly discovered effect to rescue learning and memory function in aging and AD mice.

Aim: To study the additive therapeutic effect of EE combined with MgT (EM) and the potential mechanism underlying the effects.

Materials and methods: APP/PS1 mice were treated with EE, MgT, or combination of EE and MgT (EM) and compared for restored memory function.

Results: EM was more effective in improving cognition and spatial memory than either treatment alone in either long-term (12 months, started at 3 months old, which was before disease manifestation) or short-term (3 months, started at 6 months old, which was after disease manifestation) treatment. The behavioral improvement has coincided with rescue of synaptic contacts in the hippocampal region of the AD mouse brain. Immunoblots also showed that EM but neither single treatment rescued the activity reduction in CaMKII and CREB, two important downstream molecules in the N-methyl-D-aspartate receptor (NMDAR) pathway.

Conclusion: Environmental enrichment and MgT may synergistically improve recognition and spatial memory by reducing synaptic loss and restoring the NMDAR signaling pathway in AD mice, which suggests that combination of EE and MgT may be a novel therapeutic strategy for AD.

Keywords: APP/PS1 mouse; Alzheimer's disease; N-methyl-D-aspartate receptor signaling; environmental enrichment; magnesium.

MeSH terms

  • Alzheimer Disease / complications*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Alzheimer Disease / therapy*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • CREB-Binding Protein / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Disease Models, Animal
  • Environment*
  • Humans
  • Magnesium / therapeutic use*
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory Disorders / etiology*
  • Memory Disorders / therapy*
  • Mice
  • Mice, Transgenic
  • Mutation / genetics
  • Presenilin-1 / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Recognition, Psychology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Synapses / drug effects
  • Synapses / pathology
  • Time Factors


  • Amyloid beta-Protein Precursor
  • PSEN1 protein, human
  • Presenilin-1
  • Receptors, N-Methyl-D-Aspartate
  • CREB-Binding Protein
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Magnesium