期刊
EXPERIMENTAL GERONTOLOGY
卷 41, 期 6, 页码 609-618出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exger.2006.03.018
关键词
cholinergic neurons; brain capillary endothelial cells; Alzheimer's disease; inflammation; neuroprotection
Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal Tau-inclusions and cell death of cholinergic neurons. Recent evidence indicates that the vascular system may play an important role in the development of this progressive neurodegenerative disease. The aim of this study was to observe, if brain capillary endothelial cells (BCEC) may produce and secrete factors which induce cell death of cholinergic neurons, and if this effect is counteracted by (1) NGF, MK-801 or vitamin C, (2) modulated by experimentally-induced inflammation with interleukin-1 beta and lipopolysaccharide (IL-1 beta and LPS) or (3) by blocking of different intracellular signalling pathways. Cholinergic neurons were cultivated in organotypic brain slices of the nucleus basalis of Meynert and treated with conditioned medium derived from BCEC, supplemented with different protective factors. BCEC were stimulated with IL-1 beta and LPS or different intracellular pathway inhibitors before collection of conditioned medium. Cholinergic neurons were detected by immunohistochemistry for choline-acetyltransferase. Possible effects on BCEC viability and proliferation were determined by nuclear staining, BrdU incorporation and release of nitrite and lactate-dehydrogenase. BCEC released factors that can kill cholinergic neurons. This neurotoxic effect was blocked by NGF and MK-801 (a NMDA-antagonist), but not by vitamin C. Pretreatment of BCEC with intracellular pathway inhibitors did not change the neurotoxicity, but pretreatment with IL-1 beta and LPS abolished the neurotoxic effect. In summary, BCEC produce and secrete molecules which induce excitotoxic cell death of cholinergic neurons. It is concluded that excitotoxic factors secreted by vascular cells may contribute to the development of cholinergic neurodegeneration as it occurs in Alzheimer's disease. (c) 2006 Elsevier Inc. All rights reserved.
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