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Caffeine boosts NMNAT2, an enzyme that could protect against dementia

A study by Indiana University researchers has identified 24 compounds, including Caffeine, with the potential to boost an enzyme in the brain shown to protect against dementia.

The protective effect of the enzyme, called NMNAT2, was discovered last year through research conducted at IU Bloomington. The new study is published in the journal Scientific Reports.

Previously, researchers 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.

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 Lou Gehrig's disease.

To identify substances with the potential to affect the production of the NMNAT2 enzyme in the brain, researchers screened over 1,280 compounds, including existing drugs.
A total of 24 compounds were identified as having potential to increase the production of NMNAT2 in the brain.

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.

Earlier research found that mice altered to produce misfolded tau also produced lower levels of NMNAT2.

To confirm the effect of Caffeine, 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.

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.

An additional 13 compounds were identified as having potential to lower the production of NMNAT2. These compounds are also important because understanding their role in the body could lead to new insights into how they may contribute to dementia. ( Xagena )

Source: Indiana University, 2017