The Mouse is the species of choice for many neuroscientists because of well-characterized molecular biology and chemistry of its brain, the recent widespread use of transgenic and knockout techniques, and the low cost and rapid breeding of the animal. Mice will become more important upon completion of the sequencing of the mouse genome. In 1994, Advanced Targeting Systems commercialized 192-Saporin, a reagent that causes death of cholinergic basal forebrain (CBF) neurons in the rat. A major detriment to the reagent is its lack of activity in the mouse. In our Phase I work, we created an agent that removes CBF neurons in the mouse without affecting other neurons or systems. In Phase II, it is proposed to characterize this lesioning agent and to demonstrate its usefulness as a reagent for modeling and studying neurodegenerative diseases such as Alzheimer's disease (AD). AD is a common, devastating neurodegenerative disorder characterized by progressive cognitive decline. Loss of cholinergic innervation occurs frequently and severely in patients with AD. The degree of cognitive decline has been correlated to the extent of cholinergic degeneration in the neocortex and loss of cholinergic neurons from CBF. PROPOSED COMMERCIAL APPLICATION: The primary market for a mouse p75-Saporin immunotoxin includes scientists in both academic and pharmaceutical laboratories who are involved in the study of Alzheimer's disease (AD) and other disorders of the brain. These researchers are studying neuronal controls, behavior and/or treatments that affect a wide population suffering from AD. The new mouse-specific immunotxin described in this application will be key in the discovery process because the mouse is the only other mammal, besides humans, scheduled for complete genetic sequencing. Another important asset of a mouse-specific research tool is the ability of the researcher to combine their use with transgenic models.