Proceedings of the National Academy of Sciences
May 21, 2007
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Fisher Scientists Find New Way to Inhibit Production of Neurofibrillary Tangles

The neurofibrillary tangles characteristic of Alzheimer’s disease are composed of the protein called “tau.” In fact, the quantity of tangles in the Alzheimer’s brain is closely correlated with the degree of cognitive decline, suggesting that tangles or the changes known to occur in the tau protein that precede tangles may contribute to cognitive loss in Alzheimer’s.

It is known that tangle formation results when tau is chemically changed within brain cells. This chemical change is called “hyperphosphorylation.” Hence, Alzheimer’s researchers have been seeking ways to inhibit tau hyperphosphorylation in the hope that that might be therapeutic in Alzheimer’s.

Scientists know that a protein called p35 is responsible for causing hyperphosphorylation of tau. This disease-causing activity of p35 is believed to be triggered by the buildup of beta-amyloid, a protein that is considered to be the major disease-producing factor in Alzheimer’s disease.

Dr. Wenjie Luo, a scientist at the Fisher Center (and lead author of the current work) working with Center director, Dr. Paul Greengard, Dr. Gabriela Chiosis of Memorial Sloan-Kettering Cancer Center and their colleagues recently discovered that p35 requires a protein called a “chaperone” that helps it remain stable in the cell. If it does not have this chaperone “at its side” p35 is broken down by the cell. Fisher Center scientists gave a drug-like compound, known to lower the activity of the chaperone, to mice that were genetically engineered to model Alzheimer’s disease. The compound was administered to the mice for several months. It was found to be perfectly safe in the mice, and it prevented tau hyperphosphorylation and tangle-like formations by interfering with the chaperone’s ability to stabilize p35.

This new compound or one similar to it may someday act as a drug that could prevent tangle formation in people with Alzheimer’s disease. As a result cognitive decline might be prevented or lessened.