Specific Tool for Modeling Neuronal Degeneration

Alzheimer's disease (AD) is a common, devastating neurodegenerative disorder characterized by progrcognitive decline. Loss of the cholinergic innervation of limbic structures and the neocortex occursin patients with AD. The degree of cognitive decline has been correlated to the extent of cholinergineocortex and loss of cholinergic neurons from the basal forebrain (CBF). The development of pharmacthe treatment of this disease has been hindered by the lack of a suitable animal model. Animal modeldegeneration of AD have been attempted through the use of lesioning agents--electrolytic or neurotoxnot been sufficiently specific, do not produce an efficient cell kill, or both and this has left thethe disease. The neurons of the CBF express p75, the low affinity neurotrophin receptor, and are theexpress this antigen. Recently, we have created a new cytotoxin, 192-IgU-SAP, that has been reportedspecific for rat CBF neurons that are p75 positive and produces almost complete kill of cholinergichas been reported to be a superior agent for the creation of AD-like neuronal degeneration in the rathe reagent is its lack of activity in the mouse. The mouse is the species of choice for many neuroswell-characterized molecular biology and chemistry of its brain, the recent widespread use of transgtechniques and the low cost and rapid breeding of the animal. In Phase I we will create a new reagenthe mouse to cause specific lesioning of CBF neurons and allow the development of a mouse model fordegeneration of AD.