Simulation of cortical cholinergic deficits--a novel experimental approach to study pathogenetic aspects of Alzheimer's disease.

Abstract

Cholinergic lesion paradigms have been used to study the role of the cholinergic system in cognitive function, and its implication in cognitive deficits that occur in Alzheimer's disease. In the last few years an increasing number of studies have applied neurotoxins including excitotoxins or cholinotoxins to produce reductions in cortical cholinergic activity. One of the most serious limitations of these lesion paradigms is the fact that the cytotoxins used are far from being selective to cholinergic cells. Recently, a monoclonal antibody to the low-affinity nerve growth factor (NGF) receptor, 192IgG, coupled to a cytotoxin, saporin, has been described as an efficient and selective immunotoxin for the NGF-receptor bearing cholinergic neurons in rat basal forebrain. Here we demonstrate the usefulness of 192IgG-saporin as a powerful tool for producing an animal model with selective and specific basal forebrain cholinergic lesions in rats which can be applied to simulate some neurochemical sequelae of Alzheimer's disease including cholinergic mechanisms in processing of the amyloid precursor protein, and could be of particular value to elaborate and to test therapeutical strategies compensating for the reduced cortical cholinergic input.