title: Elevation of brain magnesium prevents and reverses cognitive deficits and synaptic loss in Alzheimer's disease mouse model.
abstract: Profound synapse loss is one of the major pathological hallmarks associated with Alzheimer's disease (AD) and might underlie memory impairment. Our previous work demonstrated that the magnesium ion is a critical factor in controlling synapse density/plasticity. Here, we investigated whether elevation of brain magnesium by the use of a recently developed compound, magnesium-l-threonate (MgT), can ameliorate the AD-like pathologies and cognitive deficits in the APPswe/PS1dE9 mice, a transgenic (Tg) mouse model of AD. MgT treatment reduced Aβ plaque and prevented synapse loss and memory decline in the Tg mice. Strikingly, MgT treatment was effective even when given to the mice at the end stage of their AD-like pathological progression. To explore how elevation of brain magnesium ameliorates the AD-like pathologies in the brains of Tg mice, we studied molecules critical for APP metabolism and signaling pathways implicated in synaptic plasticity/density. In the Tg mice, the NMDAR/CREB/BDNF signaling was downregulated, whereas calpain/calcineurin/Cdk5 neurodegenerative signaling and β-secretase (BACE1) expression were upregulated. MgT treatment prevented the impairment of these signaling pathways, stabilized BACE1 expression, and reduced soluble APPβ and β-C-terminal fragments in the Tg 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. Correlation studies suggested that the protection of NMDAR signaling might underlie the stabilization of BACE1 expression. Our results suggest that elevation of brain magnesium exerts substantial synaptoprotective effects in a mouse model of AD and may have therapeutic potential for treating AD in humans.
authors: Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing 100084, China.
authors: Wei
authors: W
authors: Li
authors: Jia
authors: J
authors: Yu
authors: Yong
authors: Y
authors: Liu
authors: Xiaojie
authors: X
authors: Huang
authors: Nashat
authors: N
authors: Abumaria
authors: Ying
authors: Y
authors: Zhu
authors: Xian
authors: X
authors: Huang
authors: Wenxiang
authors: W
authors: Xiong
authors: Chi
authors: C
authors: Ren
authors: Xian-Guo
authors: XG
authors: Liu
authors: Dehua
authors: D
authors: Chui
authors: Guosong
authors: G
authors: Liu
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000209:etiology* / Q000517:prevention & control; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006801:Humans; D008274:Magnesium / Q000378:metabolism* / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D053764:Presenilin-1 / Q000235:genetics; D017729:Presynaptic Terminals / Q000473:pathology / Q000648:ultrastructure; D011930:Reaction Time / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D014018:Tissue Distribution; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002087:Butyrates; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2; D008274:Magnesium; C011369:threonic acid