Fax: 304-293-7536
Education:
Ph.D. (Biochemistry), University of Rhode Island, Kingston, RI
B.S. (Biochemistry and Chemistry), University of Pittsburgh, Pittsburgh, PA
Research Interests:
Dr. Nelson’s research is focused on uncovering the biochemical signaling pathways and protein interactions important in learning and Alzheimer’s disease. One such molecule is β-amyloid, which is a peptide found in very high levels in the brains of Alzheimer patients. Many fundamental questions about β-amyloid remain unanswered. Because Alzheimer’s disease is primarily a disease of memory, one possibility is to treat it by activating proteins, such as protein kinase C (PKC), which is known to be involved in memory. Dr. Nelson, and other BRNI collaborators, have developed a series of new lipophilic drugs that act as powerful activators of PKC epsilon, an isoform of PKC that is highly concentrated in the brain. These new drugs can greatly improve memory in transgenic mice that are commonly used as a model for Alzheimer’s disease. These drugs are being prepared for human testing. So far, there has been no evidence of any undesirable side effects even at the highest doses. If these drugs work as well in humans as they do in animals, it could be a significant step toward treating this terrible disease.
Another area of research in this laboratory is the study of interaction between β-amyloid and other proteins. Dr. Nelson has found, using mass spectrometry and a variety of biophysical techniques, that β-amyloid interacts with a number of important signaling proteins. This research suggests that β-amyloid is not acting simply as a toxin, but is interfering with the way the neuron repairs itself after injury. Identifying the normal function of β-amyloid will help explain its role in normal learning, and why learning, synapse formation, and cell viability are all impaired in patients with Alzheimer’s disease.
Another way to study this problem is by identifying protein interactions that occur specifically in Alzheimer patients. To address this problem, Dr. Nelson has developed a new way of screening for changes in protein interactions. Previously, to study protein interactions, it was always necessary to know the identity of at least one of the proteins. The protein then had to be isolated or cloned and used as “bait” to find its binding partners—a laborious and inefficient process. With our new technique, it is possible to identify and quantitate large numbers of protein interactions simultaneously without using any bait, with no prior information about what proteins are present. This new technology enables the identification of changes in signaling pathways during treatment, so its progress can be monitored. This will also accelerate the Institute’s search for the earliest pathological changes in Alzheimer’s and other dementias.
Before moving to BRNI, Dr. Nelson studied invertebrate learning and memory at the National Institutes of Health in Bethesda, Maryland, where he discovered calexcitin, a small GTP- and calcium-binding protein. In the presence of GTP and calcium, calexcitin blocks the IA potassium channel, producing a large increase in neuronal excitability that is critically important in learning. Since inhibition of potassium channels is an integral part of learning, this research could also lead to new treatments for memory disorders such as Alzheimer’s disease.
Three-dimensional model of beta-amyloid (Aβ1-42). The starting point (N-terminal) is at the left. The yellow atom is a methionine group, which is believed to be important for toxicity. Our studies of the interactions between β-amyloid and neuronal proteins are leading to new insights about its normal role in synaptic function.
Dr. Nelson has developed several new lipophilic anti-Alzheimer drugs, including DHA-CP6. DHA-CP6 is a specific activator of the epsilon isoform of protein kinase C (PKC). DHA-CP6 is very effective at protecting Alzheimer’s disease transgenic mice against neuronal injury produced by β-amyloid. Although DHA-CP6 is derived from the omega-3 polyunsaturated fatty acid docosahexaenoic acid, its mechanism of action does not involve anti-inflammatory activity, but involves the prolonged activation of PKC epsilon. In turn, PKC epsilon activates endothelin-converting enzyme (ECE), an enzyme that degrades β-amyloid.
Cholesterol binds to β-amyloid and is critically important for synaptogenesis and neuronal function. Various lifestyle-related problems including cardiovascular disease, diabetes, and obesity, all of which involve cholesterol, are statistically correlated with Alzheimer’s disease. The apolipoprotein E4 allele, which produces the mutant cholesterol-binding protein ApoE4, is a genetic risk factor for Alzheimer’s disease. This suggests that disturbances in cholesterol metabolism or signaling may be very important in Alzheimer’s disease. Dr. Nelson is studying cholesterol and oxysterols, which are oxidized cholesterol metabolites, and identifying their role in Alzheimer’s disease.
Areas of Expertise:
Biochemistry, neuroscience, protein interactions
Recent Publications:
Nelson, T. J. and Alkon, D.L. (2009) Neuroprotective versus tumorigenic protein kinase C activators. Trends in Biochemical Sciences, 34(3) 136-145.
Nelson, T. J., Cui, C., Luo, Y, and Alkon, D. (2009) Reduction of beta-amyloid levels by novel protein kinase C epsilon activators. J. Biol. Chem, 284(50) 34514-34521.
Nelson, T. J., and Alkon, D. L. (2008) Protection against beta-amyloid induced apoptosis by peptides interacting with beta-amyloid . J. Biol. Chem, Oct 26;282(43): 31238-49.
Alkon, D. L., Sun, M. K., Nelson, T. J. (2007) PKC signaling deficits: a mechanistic hypothesis for the origins of Alzheimer's disease. Trends in Pharmaceutical Sciences 28(2) 51-60.