Researchers identified the compound, normally found in tea and coffee, among a selection of 24 chemicals that target the enzyme NMNAT2 - boosting its neuroprotective function.
Other nutrients that showed efficacy in mice subjects included vitamin A, retinoic acid and wortmannin, a fungi metabolite.
“This work could help advance efforts to increase levels of this enzyme in the brain, creating a chemical 'blockade' against the debilitating effects of neurodegenerative disorders," said Dr Hui-Chen Lu, lead study author and professor of Biomolecular Science at Indiana University.
Caffeine is one of the most widely studied compounds due to its presence in popular beverages such as tea, coffee and energy drinks.
It has previously been linked to a reduced dementia risk and is known to cross the blood brain barrier. Its impact as a positive promotor of NMNAT2 has also been documented.
Caffeine criteria
The university researchers began administering caffeine to mice bred to produce lower levels of NMNAT2.
Two different doses of caffeine (20 milligrams per kilogram (mg/kg) or 50 mg/kg) or 0.9% saline were given twice, separated by 4 hours, to 3-month-old mice.
Findings revealed that mice produced the same levels of the enzyme as normal mice.
"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," said Dr Lu.
In previous work, the same team also found that NMNAT2 played a protective role by guarding neurons from stress.
In addition, the team identified a ‘chaperone-like’ role of the enzyme that prevented misfolded proteins called tau, from accumulating in the brain as "plaques" due to aging.
Possible action pathways
In trying to work out a mechanism of action to explain the observations Dr Lu and her team suggested that caffeine could boost the signalling cascade used in a cell communication pathway.
This pathway, known as the cAMP-dependent pathway, plays a fundamental role in the cellular response to many hormones and neurotransmitters.
Caffeine may act as an enzyme (phosphodiesterase) inhibitor to reduce cAMP degradation and thus increase cAMP concentrations.
Another study also showed that chronic caffeine treatment in mouse models improved memory function by reducing a chemical process of the tau protein (hyperphosphorylation).
Other compounds shown by the study to increase the production of NMNAT2 in the brain included retinoic acid although it effects were not as strong as with caffeine.
“The effect of retinoic acid could be significant since the compound derives from vitamin A,” Dr Lu added.
Source: Nature Scientific Reports
Published online ahead of print: doi:10.1038/srep43846
“Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.”
Authors: Yousuf O. Ali, Gillian Bradley & Hui-Chen Lu