Dynamic O-Glycosylation and Alzheimer's Disease

Alzheimer’s disease is among the most common and devastating of all aging diseases. In fact, 10% of people over the age of 70 and 30% of people over the age of 80 suffer from it. The mental anguish and suffering caused by Alzheimer’s disease to family members is profound. Current data suggests that Alzheimer’s disease is caused by the abnormal decay of a membrane protein on nerve cells. This degradation produces deposits on the nerve cells that lead to damage of the cell’s switching mechanisms. For example, a key protein that helps assemble the nerve cell’s skeleton, called tau protein, gets too many phosphates attached to it. This modified tau malfunctions and aggregates, ultimately leading to the death of the nerve. The cellular machinery controlling almost all living reactions in our body is controlled by molecular switches. These switches are capable of rapidly turning proteins on and off in response to signals from either the outside or inside of the cell. During the past fifty-years, scientists have found that the main switching mechanism involves the addition of phosphate molecules at specific sites on proteins. During aging, perhaps due to alterations in the use of blood sugar, or due to the slow degradation of key structural components in cells, the phosphate-mediated switching mechanisms often become damaged. Generally, these defects show up as diseases in the brain. The brain contains the most complex system of regulated pathways, and brain is absolutely dependent upon normal blood sugar. Recently, we have discovered a totally new type of very commonly used switch, in which a sugar (called 0-GlcNAc) is attached instead of phosphate. This switch seems to function opposite to the phosphate switch. Many proteins in healthy cells have this sugar attached. The presence of the sugar blocks the addition of the phosphate switches. For example the tau protein in healthy brain is normally rich in this sugar. Our premise is simple. We propose that drugs preventing the abnormal removal of this protective sugar on the brain’s proteins, would make it impossible for them to become abnormally modified by the addition of extra phosphates. We have already identified several potential drugs. The goal of this project is to test, first in animals, to see if maintaining the normal sugar modification of the proteins prevents the onset of neurodegeneration and nerve death.