Covance Blog - Sharing Innovation in Drug Development
    • Examining Tau Phosphorylation as a Potential Alzheimer's Disease Biomarker

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      Published On Nov 06 2013, 2:39 AM

      tauWe are always on the lookout to apply the latest research to our work and contribute additional findings to the scientific community. This month we will present a poster studying the regulation of Tau phosphorylation at the upcoming 2013 Society for Neuroscience conference in San Diego.

      The interest in this research was first sparked at last year's 2012 Alzheimer's Association International conference in Vancouver, Canada, where we heard discussions on the effects of anesthesia on Alzheimer's disease (AD) patients.

      Anesthesia can induce hypothermia, and this has been shown to increase the phosphorylation of a protein called Tau. Researchers want to know more about why this change happens and understand the signaling pathways involved.

      Tau proteins, mostly found in neurons of the central nervous system, have an important role in stabilizing microtubules, critical structures responsible for various movements in cells. If Tau is hyperphosphorylated, it loses effectiveness in stabilizing microtubules and starts to aggregate. Hyperphosphorylation and aggregation of Tau is observed in dementias like Alzheimer's. For this reason, Tau is considered to be a key marker in AD research.

      Our team decided to explore the pathways involved in regulating Tau. We first looked at other researchers' observations from nature. Anesthesia-induced hypothermia is closely related to the changes that happen naturally in hibernating animals. For example, hibernating Arctic ground squirrels experience a lower metabolism and a decreased body temperature; additionally the Tau protein in their brains becomes hyperphosphorylated during hibernation.

      This response to hypothermia has also been reported in an animal commonly used in research, the wild type mouse. A previous study demonstrated that an anesthetized wild type mouse with induced hypothermia had a decrease of activity in a protein called protein phosphatase 2A (PP2A). PP2A is responsible for dephosphorylating the Tau protein, but only when the portion of the enzyme that has catalytic activity (PP2AC) is modified by methylation. It has been reported that hibernating Arctic ground squirrels have decreased PP2AC methylation and increased Tau phosphorylation. Given this background, we wanted to know if decreased PP2AC methylation during hypothermia resulted in Tau hyperphosphorylation in mice.

      After performing the study, we confirmed that phosphorylated Tau levels increased in wild type mouse brains after anesthesia. However, they determined that this effect was not caused by a decrease in PP2A expression or PP2AC methylation. They also did not observe decreased levels of PPM1, a protein that is responsible for methylating PP2AC.

      Researchers had expected to find evidence for signal alteration, but these results suggest that the mechanisms of PP2A were not at play. We suspect that hypothermia-induced Tau hyperphosphorylation may alternatively function via increased Tau kinase activity, based on earlier research published by Bretteville et al.

      Ruling out this particular hypothesis will spur the research community to look at different potential pathways. At Covance, the informatics team will continue to model and build their networks to further evaluate known interactions between the different proteins. This may help determine which related pathways should be part of the next focus.

      We participated in this important research as an opportunity to make an impact in basic science and to demonstrate some of its offerings, including a wild type mouse model of Tau hyperphosphorylation and antibodies to Tau phosphorylation pathway proteins. Going forward, our researchers will continue to explore novel topics to benefit the global research community and they hope to help elucidate the pathways involved in Tau regulation.

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    About Robert Martone & Jordan Jensen, PhD

    Robert Martone is the Neuroscience Therapeutic Area Lead for the Covance Biomarker Center of Excellence. Jordan Jensen is Product Development Scientist for Antibody Products at Covance Research Products.