Selective Killing of Cholinergic Neurons by Microglial Activation in Basal Forebrain Mixed Neuronal/Glial Cultures

Abstract

Microglia activation by lipopolysaccharides (LPS) significantly decreased choline acetyltransferase−-immunopositive (ChAT+) neuron number and ChAT activity in rat primary basal forebrain mixed neuronal/glial cultures. The number of non-cholinergic (ChAT(−)) neurons was unaffected. LPS induced nitric oxide synthase (NOS) in microglia, increased the media level of the NO metabolite nitrite, and the NOS inhibitor N G-nitro-L-arginine methylester (NAME) protected the ChAT+ neurons from LPS. The combination of β-amyloid peptide (1-42) and interferon-γ (INF-γ) also increased the media nitrite level and decreased ChAT+ neuron number. Cholinergic neurons are lost early in the course of Alzheimer′s disease, and the enhanced sensitivity of these neurons to microglial activation in mixed neuronal/glial culture may be useful for modeling Alzheimer′s disease and developing therapeutic strategies to combat this disease.