Selective killing of cholinergic neurons by microglial activation in basal forebrain mixed neuronal/glial cultures.
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 Ng-nitro-L-arginine methylester (NAME) protected the ChAT+ neurons from LPS. The combination of beta-amyloid peptide (1-42) and interferon-gamma (INF-gamma) 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.
D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002795:Choline O-Acetyltransferase / Q000032:analysis / Q000378:metabolism*; D018920:Coculture Techniques; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004622:Embryo, Mammalian; D004790:Enzyme Induction / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins
D016229:Amyloid beta-Peptides; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016291:Dizocilpine Maleate; D007371:Interferon-gamma; D001120:Arginine; D019001:Nitric Oxide Synthase; D002795:Choline O-Acetyltransferase; D019331:NG-Nitroarginine Methyl Ester