Student guest post by Ron Bedford

The NYT (Kolata, 2010) recently published a story we’d all like to believe in. After their “lab’s usual end-of-the-week beer hour,” two Harvard neurology researchers noticed similarities between not only genes associated with both the innate immune system and Alzheimer’s disease (AD), but structures, characteristics, and actions of selected proteins as well. Dr. Rudolph E. Tanzi, Dr. Robert D. Moir, and their team found “striking similarities” between the well-known innate immune system protein, LL-37, and amyloid β-protein (Aβ), long considered a waste product with no apparent function, which “is believed to be the key mediator of AD pathology” (Soscia et al., 2010) What a heart-warming, at least to research scientists, story: after beers, a couple of smart guys put two and two together to notice that a protein of no apparent purpose may be associated with both the innate immune system and AD, the most common form of dementia, affecting 5.3 million patients, with costs of 172 billion dollars annually, and the seventh-leading cause of death (all U.S. statistics) (Alzheimer’s Association, 2010).

But wait, it may get even better. In BioMed Central’s Journal of Neuroinflammation, Debjani Tripathy and Paula Grammas report research suggesting that acetaminophen, a very common over-the-counter medication in the U.S., may have “a heretofore unappreciated therapeutic potential … in neurodegenerative diseases such as AD that are characterized by oxidant and inflammatory stress” (Tripathy & Grammas, 2009) A couple smart women at Texas Tech University may be onto something, too.

Soscia et al. conducted in vitro experiments to determine whether Aβ could have antimicrobial properties similar to LL-37. Their results support the hypothesis that Aβ may function in the innate immune system as an antimicrobial peptide (AMP) effective against “at least eight common and clinically relevant microorganisms.” While their research focused on the potential of β-amyloid as an AMP, the authors also acknowledge the large body of literature on the role of the innate immune system in mediating neuroinflammation related to AD and its possible association with Aβ. This is where the acetaminophen research may come in.

Tripathy and Grammas report that in addition to its association with neuroinflammation, β-amyloid evokes oxidative stress and directly damages neurons. They also state that while the interactions of all these mechanisms are not fully understood, current AD treatments focus on reducing oxidative stress and inflammation. The Texas Tech researchers pretreated rat neuronal cultures with acetaminophen and treated the cultures with menadione, “an agent that releases superoxide” or hydrogen peroxide (H2O2). The cultures pretreated with acetaminophen showed significantly improved survival compared to cultures not treated with acetaminophen (Tripathy & Grammas, 2009).

The research by Tripathy and Grammas also measured the effectiveness of acetaminophen at reducing inflammatory protein (cytokine and chemokine) release brought about by menadione treatment. Acetaminophen treated cultures showed significant reductions in the release of each of the cytokines and chemokines tested. Additionally, acetaminophen was shown to down-regulate expression of apoptotic proteins and up-regulate expression of anti-apoptotic proteins in response to menadione treatment.

Tripathy and Grammas acknowledge that much remains to be learned about the complex interactions of the innate immune system in the setting of neurodegenerative diseases. Certainly there are trade-offs to be weighed and measured between the hypothesized protective antimicrobial effects of Aβ, which was until recently regarded as a waste product, and the potential benefits of decreasing its inflammatory and oxidative effects on neuronal tissue.

No one is suggesting that in vitro rat brain cultures are the same as live human AD brain or that menadione or H2O2 perfectly represent the oxidative and inflammatory stressors that occur in conjunction with AD. But the possibility that a medication as ubiquitous as acetaminophen could potentially hold promise for the treatment of AD has to at least pique the interest of researchers in the field, except maybe those pursuing the next “latest and greatest” million dollar medication.

As always, more research is called for, both in new and cutting edge technologies as well as application of more traditional treatments in novel methodologies.

References

Alzheimer’s Association. (2010). 2010 alzheimer’s disease facts and figures. Retrieved 04/14, 2010, from http://www.alz.org/documents_custom/report_alzfactsfigures2010.pdf

Kolata, G. (2010, 3/8/2010). Infection defense may spur Alzheimer’s. The New York Times, from http://www.nytimes.com/2010/03/09/health/09alzh.html

Soscia, S. J., Kirby, J. E., Washicosky, K. J., Tucker, S. M., Ingelsson, M., Hyman, B., et al. (2010). The alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PloS One, 5(3), e9505.

Tripathy, D., & Grammas, P. (2009). Acetaminophen inhibits neuronal inflammation and protects neurons from oxidative stress. Journal of Neuroinflammation, 6, 10.