Caffeine and 23 Other Compounds Boost Enzyme That Protects Brain

Misfolded proteins have been linked to dementia, Alzheimer's, Parkinson's disease and the newly discovered compounds help untangle the proteins.

Highlights

Caffeine commonly found in chocolate, coffee boosts an enzyme that protects against dementia.
Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection.
Twenty four compounds were identified which untangle proteins in the brain due to aging.

Caffeine has the potential to boost an enzyme in the brain that protects against dementia. A study by Indiana University researchers has identified 24 compounds -- including caffeine which enhances the function of the enzyme NMNAT2.

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases.

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‘Caffeine helps boost NMNAT2 enzyme which guard neurons from stress and a chaperone function to combat misfolded proteins which may lead to Alzheimer’s, Parkinson’s disease.’

NMNATs can act as enzymes synthesizing nicotinamide adenine dinucleotide (NAD), an essential cofactor in many cellular processes as well as molecular chaperone.

"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.

Previously, Lu and colleagues found that NMNAT2 plays two roles in the brain: a protective function to guard neurons from stress and a "chaperone function" to combat misfolded proteins called tau, which accumulate in the brain as plaques due to aging. The study was the first to reveal the chaperone function in the enzyme.

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Misfolded proteins have been linked to neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases, as well as amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease.

To identify substances with the potential to affect the production of the NMNAT2 enzyme in the brain, Lu's team screened over 1,280 compounds, including existing drugs, using a method developed in her lab. A total of 24 compounds were identified as having potential to increase the production of NMNAT2 in the brain.

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One of the substances shown to increase production of the enzyme was caffeine, which also has 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.

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Another compound found to strongly boost NMNAT2 production in the brain was rolipram, an "orphaned drug" whose development as an antidepressant was discontinued in the mid-1990s. The compound 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.

Other compounds shown by the study to increase the production of NMNAT2 in the brain -- although not as strongly as caffeine or rolipram -- were ziprasidone, cantharidin, wortmannin and retinoic acid. The effect of retinoic acid could be significant since the compound derives from vitamin A, Lu said.

An additional 13 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.

Reference

Hui-Chen Lu et al., Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons, Scientific Reports (2017) http://dx.doi.org/10.1038/srep43846.

Source-Medindia