Caffeine, along with 23 other compounds, increases levels of a neuroprotective enzyme called NMNAT2 (nicotinamide mononucleotide adenylyl transferase 2), with potential implications for the treatment of dementia, new research shows.
The study, “Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons,” appeared in the journal Scientific Reports.
Previous work from the same research team, led by Hui-Chen Lu, a professor in the Department of Psychological and Brain Sciences of Indiana University at Bloomington, showed that NMNAT2 protects neurons from stress and has a “chaperone” function as it ensures that the protein tau is folded correctly. Misfolded tau forms the basis of fibrillary tangles in Alzheimer’s disease.
NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, and Parkinson’s diseases, which may help explain the protein misfolding observed in these neurodegenerative diseases. Mice engineered to produce misfolded tau also showed lower levels of NMNAT2.
In this study, the research team aimed to identify substances that could affect the production of NMNAT2 in the brain. They developed a screening platform to quantify NMNAT2 in neurons of the cerebral cortex. This platform’s sensitivity and large dynamic range enabled the screening of 1,280 compounds.
A total of 24 compounds, including caffeine, showed the potential to boost NMNAT2 levels in the brain. In mice genetically altered to produce lower levels of NMNAT2, caffeine was able to restore NMNAT2 levels to normal. Of note, caffeine was shown to improve memory in mice with high levels of misfolded tau.
Rolipram, an anti-depressant drug which was discontinued in the mid-1990s, was another compound shown to increase production of NMNAT2. Rolipram is still being studied due to its potential to protect the brain from the destructive effects of protein tangles. Among the other positive modulators of NMNAT2, retinoic acid may be relevant because the compound is derived from vitamin A.
“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,” Lu said in a press release.
Conversely, 13 compounds showed a potential to lower production of NMNAT 2 in the brain. Lu said that studying these compounds could help reveal their potential involvement in causing 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,” Lu said.