Alterations in Signal Transduction beyond Receptor Recognition

At present there are no effective drugs for the treatment of memory loss associated with Alzheimer’s disease. While some therapies have been partly successful, none have shown dramatic or consistent improvement in the daily functioning of the Alzheimer’s patient. Most of the therapies attempted thus far have been based on the demonstration that very specific nerve cells in the brain, particularly in the areas involved with memory and learning, slowly die in Alzheimer’s disease. It is believed that it is the loss of these cells which primarily account for the loss of brain function in Alzheimer’s disease. These cells which die produce and release a neurochernical called acetylcholine. Therefore, drugs to treat Alzheimer’s disease have been designed to replace the missing acetylcholine and activate the cells in the brain which normally respond to acetylcholine. It has been assumed that the cells which respond to or are activated by the neurochemical acetylcholine remain intact. Our laboratory has recently demonstrated, however, that there is a defect in the response mechanism for acetylcholine in Alzheimer’s disease. This response is not diminished in normal aging or in Parkinson’s disease, thus suggesting that this change in response to acetylcholine, and to any drugs which are given to replace missing acetylcholine, is a specific defect in Alzheimer’s disease. The present grant application proposes to examine the nature and site of alterations in the cellular response mechanisms to acetylcholine in human brain tissue from Alzheimer’s disease subjects. These types of studies are necessary for the design of drugs which may eventually become useful therapeutic agents in treating Alzheimer’s disease.