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Monitoring Dephosphorylation in Cells for Alzheimer’s Disease

Dephosphorylation, which is the removal of a phosphate group (PO32-) from an organic molecule, occurs often in the body as a normal and essential process. Perhaps the most well-known example of dephosphorylation in cells is the hydrolysis of adenosine triphosphate (ATP). The nucleophilic substitution of the phosphate group in ATP by a phosphatase enzyme results in adenosine diphosphate (ADP). This process is continually reversed by phosphorylation via a kinase enzyme. These processes are tightly regulated in cells. Unregulated dephosphorylation or phosphorylation has been linked to several diseases, including Alzheimer’s1. Alzheimer’s Disease is a neurodegenerative disease that accounts for 60 to 70% of dementia cases2. There are no cures or preventative solutions for this progressive disease that steadily strips the patient of the capability to perform bodily functions, eventually resulting in death3. Alzheimer’s Disease, which affects three out of every fifty people aged 65 and older,2 places an enormous strain not only the patient but also on the caregiver. The estimated cost of this disease in America is $100 billion a year, making it one of the most expensive health issues in our country4.

In the brain cells of Alzheimer’s patients, the protein tau is hyperphosphorylated. The deregulation of the phosphorylation is a result of the dysfunctional protein phosphatase-2A and/or protein phosphatase-2B, which are responsible for the dephosphorylation of the tau protein1. The tau hypothesis suggests that it is this deregulation that is in fact the cause of the disease development5. The accumulation of phosphorylated tau proteins results in a neurofibrillary tangle, which further results in neuron death. As the diseased neurons die, the brain shrinks intensely.

 

Deregulated Tau Phosphorylation

Phosphatasegoes toTangles

 

Figure 1: The progression of the tau hypothesis. Healthy neurons should have straightened fibers. Diseased neurons die off as they become more tangled.

 

brain

Figure 2: The Alzheimer’s Association provides a plethora of information for Alzheimer’s patients. In this diagram, they demonstrate the physical degeneration of the brain.

 

At the University of Maryland Baltimore County, Dr. Zeev Rosenzweig’s laboratory fabricates nanoscale luminescent probes for biomedical applications. In this lab, a group of students and I are currently developing fluorescent probes for intracellular analysis of phosphatases. The nanoscale fluorescent probes are composed of luminescent indium phosphide quantum dots.  These nanomaterials are introduced as non-toxic alternatives to commonly used cadmium containing quantum dots. This probe would function as a spatially accurate real-time monitor of biological reactions, such as dephosphorylation. The quantum dot based fluorescent probe would allow us to determine the activity of the phosphatase enzyme as a function of fluorescence intensity. The rate of dephosphorylation is related to the phosphatase activity. By measuring the rate of dephosphorylation (or the lack of it), one could quantify the progression of the tau hypothesis within cells.

Sources

  1. Gong, C. X., Grundke-Igbal, I., Igbal K. Dephosphorylation of Alzheimer’s disease abnormally phosphorylated tau by protein phosphatase-2A. Nueroscience (1994). 61. 4: 765-72.
  2. Burns, A., Iliffe, S. Alzheimer’s Disease—A Clinical Review. BMJ (2009). 338:158.
  3. About Alzheimer’s Disease: Symptoms. National Institute on Aging. Web. 21 Jul 2016.
  4. Meek, P.D., McKeithan, K., Shumock, G.T. Economic considerations in Alzheimer’s disease. Pharmacotherapy (1998). 18: 68-73.
  5. Mudher, A., Lovestone, S. Alzheimer’s Disease-do Tauists and Baptists finally shake hands? Trends Neurosci (2002). 25. 1:22-6.