By Milton Bertrand

According to a new study published in the journal Scientific Reports by Indiana University (IU), caffeine has the potential to boost an enzyme in the brain shown to protect against dementia. The protective effect of the enzyme, called NMNAT2, was discovered in 2016 through research conducted at IU Bloomington.

"This work could help advance efforts to develop drugs that increase levels of this enzyme in the brain, creating a chemical 'blockade' against the debilitating effects of neurodegenerative disorders," said Hui-Chen Lu, who led the study. Lu is a Gill Professor in the Linda and Jack Gill Center for Bio-molecular Science and the Department of Psychological and Brain Sciences, a part of the IU Bloomington College of Arts and Sciences.

Previously, the enzyme NMNAT2 was found to play two roles in the brain: a protective function to guard neurons from stress and a "chaperone function" to combat misfolded proteins called tau; tau proteins accumulate in the brain as "plaques" due to aging. Such study was the first to reveal the "chaperone function" of the enzyme.

When proteins are misfolded proteins, they are linked to neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, as well as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. Alzheimer's disease is the most common form of these disorders; it affects over 5.4 million Americans; such number is expected to rise as the population ages.

 A total of 1,280 compounds, including existing drugs, using a method developed in Lu’s Lab were screened. However, a total of 24 compounds were identified as having potential to increase the production of NMNAT2 in the brain.

Caffeine was one of the compounds shown to increase production of the enzyme; it has also been shown to improve memory function in mice genetically modified to produce high levels of misfolded tau proteins. Lu's earlier research found that mice altered to produce misfolded tau also produced lower levels of NMNAT2.

To confirm the effect of caffeine, IU researchers administered caffeine to mice modified to produce lower levels of NMNAT2. As a result, the mice began to produce the same levels of the enzyme as normal mice. Rolipram was another compound found to strongly boost NMNAT2 production in the brain an "orphaned drug" whose development as an antidepressant was discontinued in the mid-1990s. The compound still remains of interest to brain researchers due to several other studies also showing evidence it could reduce the impact of tangled proteins in the brain. There were other compounds in the study that increased the production of NMNAT2 in the brain -- although not as strongly as caffeine or Rolipram. Ziprasidone, cantharidin, wortmannin and retinoic acid were showed some effects. The effect of retinoic acid could be significant since the compound derives from vitamin A, Lu said.

In addition, 13 other compounds were identified as having potential to lower the production of NMNAT2. Lu said these compounds are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia.

"Increasing our knowledge about the pathways in the brain that appear to naturally cause the decline of this necessary protein is equally as important as identifying compounds that could play a role in future treatment of these debilitating mental disorders," she said.