New Scholar Award in Aging
Hui Zheng, Ph. D.
Baylor College of Medicine

An Inducible Gene Knockout System for Alzheimer's Disease and Aging Research.

The transgenic and gene knockout technology has proved to be a powerful system to elucidate in vivo functions of target genes and to establish mouse models of human diseases. However, the conventional approach introduces modifications in mouse germline, which may lead to adverse effects or may be fully compensated in development. Thus, the function of these genetic modifications in adults and during aging cannot be appropriately evaluated. Therefore, efficient introduction of somatic modifications, including both gene activation and gene knockout, in a given gene, at a given time, in a given tissue, is both essential and highly desirable for aging research.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly. It is characterized by the deposition of b-amyloid plaques and loss of neurons in affected individuals. Genetic and biochemical analysis have provided compelling evidence that the generation and accumulation of Ab42, a peptide of 42 amino acids in length and deposited in the b-amyloid plaques, plays a crucial role in AD pathogenesis. However, it is not clear whether it is the intracellular or secreted form of the peptide or whether it is the soluble or precipitated peptide that is toxic to the neurons.

Mutations in Presenilin-1 (PS1) are linked to early onset of familial Alzheimer's disease (FAD) and are shown to foster the production of Ab42. Presented as an aging related protein, PS1 is also required for mammalian embryonic development as PS1 knockout mice die perinatally. In light of the essential roles of Ab42 and PS1 in Alzheimer's disease pathogenesis and a great demand for an inducible transgenic and gene knockout system for aging research, we propose to accomplish the following research objectives: 1) Develop a spatio-temporally controlled gene regulation system so that the target gene can be either induced or inactivated in the central nervous system (CNS) at a defined time frame. To achieve this, we plan to use the powerful "gene switch" system in which the genetic modifications will only occur following the application of the synthetic steroid mifepristone (RU486); 2) Generate transgenic lines expressing either intracellular or secreted Ab42 in adult brain for various lengths of time to determine the effect of various forms of Ab42, i.e., intracellular vs. extracellular, soluble vs. insoluble; and 3) Use the transgenic lines to generate inducible knockout of PS1 and determine its function in adult CNS.

Contact Dr. Zheng.