Caffeine protects against neurodegenerative disorders

Enzyme called NMNAT2 (nicotinamide mononucleotide adenylyl transferase 2)  is a key neuronal maintenance factor that provides potent neuroprotection against neurological disorders: Alzheimer’s, Huntington’s, Parkinson’s diseases. There are two known mechanism of action of NMNAT2 : 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. 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. Alzheimer’s disease, the most common form of these disorders, affects over 5.4 million people in USA. Most importantly, increased level of NMNAT2 protects against neurological disorders. To identify molecules that can boost NMNAT2, reserchears developed a high-throughput screening platform to detect NMNAT2 levels in cortical neurons and tested 1280 chemical compounds to identify NMNAT2 modulators. 24 of them were shown to increase the production of NMNAT2 in the brain. One of the NMNAT2 positive modulators was caffeine, which also has been shown to improve memory function in mice genetically modified to produce high levels of misfolded tau proteins. To confirm the positive effect of caffeine, researchers administered caffeine to genetically modified mice with lower levels of NMNAT2. As a result, the mice began to produce the same levels of the enzyme as normal mice. An additional 13 compounds were identified as having potential to lower the production of NMNAT2. The are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia.
Ali, Y. O. et al. Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Sci. Rep. 7, 43846