A Weapon Against Dementia in Your Coffeepot

April 6, 2017

The caffeine in your morning cup of java could pack a neuroprotective punch.

RESEARCH UPDATE

Some years ago, the hepatology community was abuzz when it was confirmed that coffee consumption could keep fatty liver disease in check.1 Now, research from Indiana University suggests that caffeine-the magic ingredient in coffee-might keep dementia at bay. Specifically, caffeine may boost the production of an enzyme important to brain function, affording protection against tauopathies such as frontotemporal dementia.2

The enzyme in question is nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2). Levels have been shown to be significantly reduced in neurological diseases such as Alzheimer, Parkinson, and Huntington. Overexpression, in turn, appears to be neuroprotective in experimental models.3 The enzyme acts as a molecular chaperone against tau.

Neuroprotective enzyme boosters

To identify substances that could boost production of NMNAT2, the research team, headed by Hui-Chen Lu, PhD, of the Department of Psychological and Brain Sciences at Indiana University, screened more than 1280 compounds. They ultimately found 24 with the potential to increase NMNAT2. In further narrowing the list via in vitro experiments, 6 compounds were identified as effective NMNAT2 up-regulators: caffeine, rolipram, ziprasidone, cantharidin, wortmannin, and retinoic acid.

The phosphodiesterase inhibitors caffeine and rolipram were the most effective of the 6 compounds identified. The researchers noted that phosphodiesterase inhibitors reduce cyclic adenosine monophosphate (cAMP) degradation and that NMNAT2 up-regulation was spurred by an increase of cAMP or excitatory neurotransmission.

The researchers went on to test the value of caffeine as an NMNAT2 up-regulator in vivo. In one experiment, wild-type and heterozygous mice (aged 3 months) were intraperitoneally injected with 2 doses of 20 mg/kg or 50 mg/kg of caffeine or saline, with the second dose administered 4 hours after the first. Four hours after administration of the second dose, NMNAT2 levels in the cortex were evaluated via Western blot analysis. Caffeine treatment resulted in a dose-dependent increase in NMNAT2 levels.

Impact of caffeine

In a second experiment, the impact of caffeine on NMNAT2 up-regulation was examined in a murine model of frontotemporal dementia and Parkinsonism: rTg4510 transgenic mice. The researchers had previously shown that NMNAT2 was greatly reduced in the cortex of this tauopathy model,3 and so they injected 50 mg/kg of caffeine or saline into rTg4510 transgenic mice and healthy littermates in the same manner as in the first experiment. The result: the NMNAT2 levels in the tauopathy models increased to be on par with those of the healthy mice.

Clinical implications

Other research has shown that caffeine may be protective against dementia. Namely, the Cardiovascular Risk Factors, Aging and Dementia study showed an association between drinking 3 to 5 cups of caffeinated coffee per day at midlife and a 65% decreased risk of dementia and Alzheimer disease in late life.4 Although the current research raises the question, “Well, how much caffeinated coffee should I be drinking then?” the ultimate goals of the study and the team’s ongoing research, according to Dr. Lu, are to increase knowledge about neurochemical pathways that compromise NMNAT2 expression and to identify compounds that may figure into future treatments for tauopathy-driven dementias.

References:

1. Saab S, Mallam D, Cox GA 2nd, Tong MJ. Impact of coffee on liver diseases: a systematic review. Liver Int. 2014;34:495-504.

2. Ali YO, Bradley G, Lu HC. Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons. Sci Rep. 2017;7:43846.

3. Ljungberg MC, Ali YO, Zhu J, et al. CREB-activity and nmnat2 transcription are down-regulated prior to neurodegeneration, while NMNAT2 over-expression is neuroprotective, in a mouse model of human tauopathy. Hum Mol Genet. 2012;21:251-267.

4. Eskelinen MH, Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer’s disease. J Alzheimers Dis. 2010;20(suppl 1):S167-S174.