The cholinergic mouse

Scripps Research Institute, La Jolla CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Our ability to develop treatments for Alzheimer's disease has been limited by our lack of understanding of the etiology of this disorder. One way of addressing the problem has been to develop animal models of this disease and to use these to test hypotheses concerning the origin and progression of the neural degeneration. Although the loss of cholinergic neurons is no longer believed to be the initiating event in Alzheimer's disease, functional deficits in the cholinergic system are an important component of this disorder. Here we propose to produce a transgenic mouse model ("the cholinergic mouse") that would permit the regulated expression of genes in cholinergic cells. This model should prove useful in identifying the factors that promote cholinergic neuronal survival and the maintenance of cholinergic synaptic connections. We will use the promoter for choline acetyltransferase (CHAT) to drive the expression of the tetracycline transactivator. When mated to a distinct transgenic line containing a candidate gene whose transcription is regulated by the tetracycline operator, the resulting mice should express the candidate gene exclusively in cholinergic neurons in the presence of the inducer, tetracycline. The availability of "the cholinergic mouse" should help neuroscientists tackle Alzheimer's by facilitating the creation of new models for this disease and by expanding the utility of existing models. As new loci related to the origin or progression of Alzheimer's emerge from our improved understanding of the human genome, these genes or altered versions of these genes can be specifically re-inserted into subsets of neurons to assess their effects. Use of "the cholinergic mouse" would be superior to currently available systems, which express genes in larger collections of cells. Through these efforts, we hope to create a genetic tool that will lead to an improved understanding of cholinergic neuronal function and accelerate the development of therapeutics for the patient with Alzheimer's disease.