title: Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer's disease mouse model.
abstract: BACKGROUND
  Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease, which might underlie memory impairment. Our previous work demonstrates that magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we tested whether elevation of brain magnesium, using a recently developed compound (magnesium-L-threonate, MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic mouse model of Alzheimer's disease.
  
  
  RESULTS
  MgT treatment reduced Aβ-plaque, prevented synapse loss and memory decline in the transgenic mice. Strikingly, MgT treatment was effective even when the treatment was given to the mice at the end-stage of their Alzheimer's disease-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brain of transgenic mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the transgenic mice, the NMDAR signaling pathway was downregulated, while the BACE1 expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression and reduced sAPPβ and β-CTF in the transgenic mice. At the molecular level, elevation of extracellular magnesium prevented the high Aβ-induced reductions in synaptic NMDARs by preventing calcineurin overactivation in hippocampal slices.
  
  
  CONCLUSIONS
  Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of Alzheimer's disease, and hence it might have therapeutic potential for treating Alzheimer's disease.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Huang
authors.forename: Nashat
authors.initials: N
authors.lastname: Abumaria
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.forename: Xian
authors.initials: X
authors.lastname: Huang
authors.forename: Wenxiang
authors.initials: W
authors.lastname: Xiong
authors.forename: Chi
authors.initials: C
authors.lastname: Ren
authors.forename: Xian-Guo
authors.initials: XG
authors.lastname: Liu
authors.forename: Dehua
authors.initials: D
authors.lastname: Chui
authors.affiliation: School of Medicine, Tsinghua University, Beijing, China. liu.guosong@gmail.com.
authors.forename: Guosong
authors.initials: G
authors.lastname: Liu
mesh_terms: D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007858:Learning / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D002087:Butyrates; D016194:Receptors, N-Methyl-D-Aspartate; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; C011369:threonic acid