Journal of neuroscience research
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Nicotine and other nicotinic acetylcholine receptor agonists have been shown to exert neuroprotective actions in vivo and in vitro by an as yet unknown mechanism. Even the identification of the subtype of nicotinic receptor(s) mediating this action has not been determined. In neural cell lines, the induction of cytoprotection often requires exposure to nicotine for up to 24 hr to produce a full protective effect. ⋯ Under similar conditions of incubation, the nicotinic receptor agonist cytisine (that was least effective in terms of neuroprotection) failed to increase the number of [(125)I]alphaBGT binding sites. Cells expressing increased levels of cell surface [(125)I]alphaBGT binding sites received added neuroprotective benefit from nicotine. Thus the induced upregulation of the alpha7 subtype of nicotinic receptors during chronic exposure to nicotine may be responsible for the drug's neuroprotective action.
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The main objective of the present study was to develop an alternative singly-transgenic (tg) hAPP model where amyloid deposition will occur at an earlier age. For this purpose, we generated lines of tg mice expressing hAPP751 cDNA containing the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the murine (m)Thy-1 gene (mThy1-hAPP751). In the brains of the highest (line 41) and intermediate (lines 16 and 11) expressers, high levels of hAPP expression were found in neurons in layers 4-5 of the neocortex, hippocampal CA1 and olfactory bulb. ⋯ Mice from line 11 developed diffuse amyloid deposits at 11 months of age, whereas mice from line 16 did not show evidence of amyloid deposition. Analysis of Abeta by ELISA showed that levels of Abeta(1-40) were higher in mice that did not show any amyloid deposits (line 16), whereas Abeta(1-42) was the predominant species in tg animals from the lines showing plaque formation (lines 41 and 11). Taken together this study indicates that early onset plaque formation depends on levels of Abeta(1-42).
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Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family and regulates the survival, differentiation, and maintenance of function in different neuronal populations. BDNF is strongly expressed in hypothalamic neurons, where it exerts long- or short-lasting actions. Because glutamate has been associated with regulations of hypothalamic hormones, we examined the regulation of the four promoters of the BDNF gene by glutamate in fetal hypothalamic neurons. ⋯ Actinomycin D blocked the increase of all transcripts, whereas cycloheximide treatment inhibited stimulation only of exon I and II mRNAs. Trk B mRNA was rapidly and transiently reduced after glutamate application. Our results demonstrate that glutamate 1) regulates BDNF mRNA expression at an early developmental stage in hypothalamic neurons and 2) exerts a differential regulation of BDNF transcripts.