Researchers suggest that the disease is caused by an autoimmune response whereby the enzyme arginase begins catabolising abnormally high amounts of arginine, a semi-essential amino acid. This leads to a deficinecy in arginine in the brain cells, and previous studies have shown that sustained arginine deprivation leads to brain cell death.
But the new study, led by Matthew Kan, showed that blocking the excessive breakdown of arginine, with a drug currently being investigated for cancer treatment, prevented the formation of brain plaques – a characteristic of Alzheimer’s disease – and the associated memory loss.
"All of this suggests to us that if you can block this local process of amino acid deprivation, then you can protect -- the mouse, at least -- from Alzheimer's disease," said Kan.
Joining the dots
The findings, published yesterday in the Journal of Neuroscience, were welcomed by Dr James Pickett, Head of Research at Alzheimer’s Society, who said it "[joined] some of the dots in our incomplete understanding of the processes that cause Alzheimer’s disease, in particular around the role played by the immune system."
Co-author Carol Colton said that the findings were promising in terms of developing effective therapies - but she did not recommend arginine supplementation due to bioavailability issues. The blood-brain barrier would prevent the arginine from entering the brain, and even if it did get through the arginine would still be broken down by the enzyme arginase.
Blocking arginase is therefore the crux of any potential therapies: "If indeed arginine consumption is so important to the disease process, maybe we could block it and reverse the disease," said Colton,
The findings by Duke University scientists go against previous suggestions for the cause of Alzheimer’s disease, which held that the protein fragment beta-amyloid was key to the disease.
"It's surprising, because [suppression of the immune system is] not what the field has been thinking is happening in Alzheimer's," Kan said.
The researchers used transgenic mice that have been bred to develop neuropathology, mimicking the progression of Alzheimer’s in humans through the formation of sticky protein brain plaques, tau protein build-up, memory impairment and neuron death in the hippocampus.
At age 6-8 weeks, the mice were treated with 10mg/kg of Difluoromethylornithine (DFMO), or saline as a control.
After 12 weeks of treatment the scientists tested how the mice fared for memory and learning in a two-day water maze. The brains were then analysed – mice treated with DFMO had fewer plaque formations and performed better in memory tests, while high quantities of arginase was found in the mice brains where cells had died.
“Mice treated with DFMO plus putrescine demonstrated significantly improved acquisition and recall compared with vehicle (putrescine only)-treated ... mice, suggesting that blockade of arginine catabolism reverses the behavioral phenotype of memory loss found in mice.”
Alzheimer's specialists have welcomed the findings of the study but called for more research in human trials.
Dr James Pickett, Head of Research at Alzheimer’s Society said: "The next step would be to show that targeting arginine metabolism in the brain can reduce the death of brain cells, as this was not shown in the current study.”
According to the Alzheimer’s Society, 60,000 deaths a year are directly attributable to dementia.
Source: Journal of Neuroscience,
First published online 15 April 2015, doi: 10.1523/JNEUROSCI.4668-14.2015
"Arginine Deprivation and Immune Suppression in a Mouse Model of Alzheimer’s Disease"
Authors: M. J. Kan, J. E. Lee et al.