While too little calcium can trigger bone problems, insufficient magnesium may spell trouble for your brain, suggests a study published in the January 28 issue of Neuron. An international research team led by Guosong Liu of Tsinghua University, Beijing, showed that raising brain magnesium with a new oral compound enhanced learning and memory in young and old rats. The data linked the cognitive benefits to magnesium’s ability to induce changes in NMDA receptors that promote long-term potentiation. “Not only do we increase the number of synapses, but we also enhance the function of individual synapses,” said Liu, who launched the project while heading a lab at MIT.

Aside from a yearning to “do something important for society,” several observations led Liu to place his career bets on magnesium. First came the scientific rationale. Long interested in synapse function, he and MIT colleagues discovered that increasing magnesium concentration in hippocampal cultures could enhance synaptic plasticity, the molecular basis for learning and memory (Slutsky et al., 2004). Then there’s the broader conceptual tidbit: On the evolutionary tree, higher animals have more brain magnesium even though blood concentrations of the ion are similar across species, Liu said. Furthermore, less than one-third of Americans get enough dietary magnesium (see government survey), and magnesium intake tends to decrease in seniors (Ford and Mokdad, 2003), fueling speculation that inadequate magnesium could underlie age-related cognitive decline. This notion draws support from small autopsy studies that found lower brain magnesium levels in people with Alzheimer disease (Andrási et al., 2000; Andrási et al., 2005).

Led by joint first authors Inna Slutsky, now at Tel Aviv University in Israel, and Nashat Abumaria of Tsinghua University, the researchers began by screening for magnesium compounds that looked promising for in-vivo studies. This proved a formidable task. Ion pumps carefully regulate the amount of magnesium that gets into the brain, and the vast majority of oral compounds tested had no appreciable effect on this parameter, as judged by cerebrospinal fluid (CSF) analysis before the rats were treated, and 12 and 24 days afterward. The researchers did find one compound, magnesium threonate (MgT), that had decent bioavailability and raised CSF magnesium levels by 7-15 percent at 24 days. Among other magnesium compounds with similar bioavailability, MgT was the only one that improved short- and long-term memory in aging (18-month-old) rats. In other behavioral studies, MgT treatment boosted spatial working memory and long-term memory in both young (two months) and old (22 months) rats. In the young animals, the cognitive benefits became apparent six days after the start of treatment and remained for at least a month after treatment ended. In the older animals, the compound worked differently, but still looked promising. For this group, the cognitive boost came 12 days into the treatment but waned considerably a few weeks after MgT treatment was interrupted. However, after a 30-day hiatus, re-introduction of MgT caused memory performance to spike once again in the old rats.

To address what mechanism might be at play, the researchers focused on NMDA receptors. Brain magnesium regulates the voltage-dependent block of these receptors, which are critical for synaptic plasticity. Liu and colleagues treated hippocampal slices with elevated magnesium and saw increased numbers of functional synapses. In biochemical analyses of brain tissue from MgT-treated rats, the researchers found elevated levels of NMDA receptor 2B (NR2B) and increased activation of downstream signaling molecules CamKII and CREB. Overall, elevated magnesium “induced reconfiguration of synaptic networks from a small number of synapses with high release probability to a larger number of synapses with low release probability,” the authors wrote. In a final series of experiments, the team showed that the synaptic changes correlated with improvements in learning and memory as charted across an on/off treatment time course.

The authors speculate that an increase in intracellular magnesium could alter calcium signaling. Magnesium is the only endogenous calcium inhibitor, Liu said, making it a good prospect for countering dysfunctional calcium signaling, which has been implicated in AD many times (see ARF Live Discussion).

Liu and colleagues have preliminary data showing that MgT can prevent memory loss and premature death in AD model mice, he told ARF. They plan to test the compound in animal models for Parkinson disease, which is also characterized by synapse loss. In addition, Liu said, he and colleagues have promising data from an ongoing clinical study of more than 300 people that investigates magnesium dysfunction in AD patients.

Still, efforts to move MgT into human testing could face challenges stemming from the large effective dose (604 mg/kg/d, which equates to 50 mg magnesium) identified in the current studies, as Ashley Bush of the Mental Health Research Institute, Victoria, Australia, notes in an accompanying editorial. Correcting for body surface area, “the estimated human dose for early phase trials would be 98 mg/kg/d or about 7 grams of MgT per day, which could be an impractical dose for a trial,” he wrote.

Nevertheless, Bush believes MgT “represents a very promising lead for drug development, and shows that the blood-brain barrier can be pharmacologically surmounted to therapeutically increase the uptake of metal ions by the brain.” He and colleagues have characterized PBT2, a zinc/copper ionophore that boosts cognition in AD transgenic mice (Adlard et al., 2008 and ARF related news story) and has shown some benefit in a small Phase 2a trial (Lannfelt et al., 2008; see also ARF related news story). Bush is co-founder of Prana Biotechnology Ltd., the Australian biotech company that sponsored the trial.—Esther Landhuis

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References

Webinar Citations

  1. Calcium in AD Pathogenesis

News Citations

  1. Improving Cognition in Mice: Copper Ionophore Shows Some Mettle
  2. Anti-Amyloid Drug Clears Phase 2a Hurdle

Paper Citations

  1. . Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity. Neuron. 2004 Dec 2;44(5):835-49. PubMed.
  2. . Dietary magnesium intake in a national sample of US adults. J Nutr. 2003 Sep;133(9):2879-82. PubMed.
  3. . Disturbances of magnesium concentrations in various brain areas in Alzheimer's disease. Magnes Res. 2000 Sep;13(3):189-96. PubMed.
  4. . Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis. 2005 Aug;7(4):273-84. PubMed.
  5. . Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008 Jul 10;59(1):43-55. PubMed.
  6. . Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008 Sep;7(9):779-86. PubMed.

External Citations

  1. government survey

Further Reading

Papers

  1. . Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer's disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2008 Sep;7(9):779-86. PubMed.
  2. . Magnesium supplementation in the treatment of dementia patients. Med Hypotheses. 2006;67(5):1223-5. PubMed.
  3. . Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron. 2008 Jul 10;59(1):43-55. PubMed.

Primary Papers

  1. . Kalzium ist nicht alles. Neuron. 2010 Jan 28;65(2):143-4. PubMed.
  2. . Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77. PubMed.