Tumor necrosis factor-α triggers cell death of sensitized potassium chloride-stimulated cholinergic neurons

• Published in: Brain research. Molecular brain research. 2003-05, Vol.113 (1), p.78-85
• Main Authors: Zassler, Birgit, Weis, Carla, Humpel, Christian
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Acetylcholinesterase; Acetylcholinesterase - drug effects; Acetylcholinesterase - metabolism; Ageing, cell death; Aging - metabolism; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Animals; Basal nucleus of Meynert; Basal Nucleus of Meynert - drug effects; Basal Nucleus of Meynert - metabolism; Basal Nucleus of Meynert - physiopathology; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell physiology; Cell Survival - drug effects; Cell Survival - physiology; Cells, Cultured; Choline acetyltransferase; Choline O-Acetyltransferase - drug effects; Choline O-Acetyltransferase - metabolism; Cholinergic Fibers - drug effects; Cholinergic Fibers - metabolism; Fundamental and applied biological sciences. Psychology; Growth Cones - drug effects; Growth Cones - metabolism; Growth Substances - metabolism; Growth Substances - pharmacology; Immunohistochemistry; Inflammation - complications; Male; Molecular and cellular biology; Potassium chloride; Potassium Chloride - pharmacology; Rats; Rats, Sprague-Dawley; Retrograde Degeneration - chemically induced; Retrograde Degeneration - metabolism; Retrograde Degeneration - physiopathology; Tumor Necrosis Factor-alpha - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor necrosis factor-α
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/S0169-328X(03)00092-5

Cell death of cholinergic neurons of the basal forebrain plays an important role in neurodegenerative disorders, such as Alzheimer’s disease. Inflammatory cytokines, such as, for example, tumor necrosis factor-α (TNF-α), may be involved in these neurodegenerative processes. The aim of this project was to study the role of TNF-α in the survival and nerve fiber growth of cholinergic neurons of the basal nucleus of Meynert in organotypic brain slices and in adult rats. Cholinergic neurons were visualized by immunohistochemistry for the enzyme choline acetyltransferase and nerve fibers by histochemistry for the enzyme acetylcholinesterase. When co-slices of basal nucleus of Meynert and neocortex were sensitized for 15 min with 30 mM potassium chloride and subsequently incubated for 1 week with 20 ng/ml TNF-α, cholinergic neurons and nerve fibers markedly degenerated. Incubation with different growth factors rescued the loss of cholinergic cell bodies and cholinergic nerve fibers. Injection of 30 mM potassium chloride and 50 ng TNF-α into four defined cortical regions of anesthetized adult rats resulted in predominant cell death of cholinergic neurons on the ipsilateral side. In conclusion, our data show that TNF-α potentiated cell death of cholinergic neurons possibly via retrograde axonal damage in vitro and in vivo. Cortical overactivation combined with an increased expression of pro-inflammatory cytokines may contribute to the cell death observed in Alzheimer’s disease and ageing.