Long-term survival of basal forebrain cholinergic neurons in vivo: A test of the neurotrophic hypothesis

Abstract

The degeneration of basal forebrain cholinergic neurons with corresponding reductions in cholinergic innervation to the neocortex is a characteristic neuropathological feature of Alzheimer's disease. The mechanism responsible for the atrophy and death of these neurons is unknown, but animal studies utilizing a variety of lesioning techniques have demonstrated the dependence of these neurons on target cell-derived neurotrophic factors, most notably nerve growth factor. We have utilized the prenatal administration of methylazoxymethanol acetate (MAM) as a noninvasive lesioning technique to test the theory that cholinergic neurons are dependent on neurotrophic growth factors for survival. The administration of moderate dosages of MAM during the period of cortical neurogenesis results in the ablation of 40-70% of total cortical neurons. Administration of MAM however, had no significant effect on the genesis of basal forebrain cholinergic neurons as determined by choline acetyltransferase and nerve growth factor immunocytochemistry, and verified by cholinergic enzymatic assays. We also extensively characterized the specificity of lesions by morphological and neurochemical methods in two month-old animals and subsequently followed the lesioned animals until 20 months of age for signs of basal forebrain neuronal degeneration. In contrast to previous reports, the removal of over 50% of the total population of target cells of basal forebrain projections does not result in either atrophy or degeneration of significant numbers of basal forebrain cholinergic neurons. In addition, immunocytochemical evidence reveals the absence of an injury response in the brains of MAM-treated animals. These observations, together with Northern hybridization data demonstrating no significant increase in the expression of neurotrophic factor, eliminate compensatory neurotrophic support as a means of promoting basal forebrain neuronal survival. These data contradict the "neurotrophic hypothesis" as an etiological factor in basal forebrain neuronal degeneration observed in Alzheimer's disease, and support the theory that the initial neuropathological insult may be to basal forebrain cholinergic neurons.