Molecular cloning of m1 receptor-inducible genes

Projektdetails:

Projektbeschreibung

The clinical symptoms of Alzheimer’s disease are most closely related to the massive loss of synapses, the connections that neurons use for communication with the aid of chemical neurotransmitters. There are several such neurotransmitter systems in the brain, and most of them are damaged to a certain degree in Alzheimer’s disease brains. Among the most heavily damaged systems is the cholinergic system that plays a major role in learning and memory. In addition, this system seems to be involved in the regulation of the cleavage of the amyloid precursor protein, and thus in amyloid formation. It is likely that many of the clinical signs of Alzheimer’s disease are caused by the loss of cholinergic synapses.

So far Dr. Nitsch has cloned eight activity-dependent neuronal genes, with an intriguing variety of functions including the regulation of gene expression, cell growth, and most importantly the feedback regulation of neurotransmission. As one example, the gene encoding for the enzyme that degrades the neurotransmitter acetylcholine is activated by acetylcholine, thus providing a feedback loop to terminate excess neurotransmission. This feedback mechanism may be the basis for the limited efficacy of the current drugs.

The aim of this project is to lead the way for the design of improved drugs that have the beneficial effects of acetylcholine replacement without the unwanted side effects of even further acceleration of the degradation of acetylcholine. In addition to these important novel insights into the cellular effects of drugs currently tested in Alzheimer’s disease patients, the experiments outlined in this project will open a new way into therapeutic uses of pharmacological modulation of neuronal gene expression, and thus brain function.