OBJECTIVE Alzheimer disease(AD) is the most common type of dementia and is featured by the accumulation of β-amyloid peptide(Aβ) in the brain. The Alpha 7 nicotinic acetylcholine receptor family(α7 nAChR) was widel...OBJECTIVE Alzheimer disease(AD) is the most common type of dementia and is featured by the accumulation of β-amyloid peptide(Aβ) in the brain. The Alpha 7 nicotinic acetylcholine receptor family(α7 nAChR) was widely considered to interact with that Aβ, mediate neuroprotection and improve cognitive performance. However, the mechanisms underlying these interactions remain elusive. The present study aimed to determine how this interaction contribute to AD pathology. METHODS In vitro model of AD(primary culture of mice hippocampus treated with Aβ) and in vivo, a mouse model of AD(APPswe/PSEN1 d E9 double transgenic mice, APP/PS1_DT mice) were used to study to the possible inter-action of α7 nAChR and Aβ in the pathogenesis of AD. In vitro experiments, the primary hippocampal neurons cell was exposed to Aβ1-42 peptides in combination with PNU. In vivo experiments, different drugs/operations was applied to APP/PS1_DT mice for setting up of the following groups: WP group, wild-type C57 mice treated with PNU(α7 nAChR specific agonist);AP group, APP/PS1_DT mice treated with PNU;APP/PS1 group, the APP/PS1_DT mice injected intraperitoneally with the same amount of normal saline for 5 d;Control group, wild-type C57 mice injected intraperitoneally with the same amount of normal saline for 5 d. A transmission electron microscope was used to observed the synaptic morphological changes of hippocampal neurons. Reverse transcription quantitative PCR(RT-q PCR) and Western blot analysis were used to detect the expression levels of synaptic-associated proteins(SYN, SNAP25 etc). The learning and memory abilities of mice were detected by Morris water maze. RESULTS In vitro, it was found that α7 nAChR acts as an anti-Aβ-induced synaptic injury to nerve cell by increased the expression of synaptic-associated proteins and attenuated apoptosis induced by Aβ oligomers. In vivo, α7 nAChR attenuated synaptic loss induced by Aβ1-42, reduced the deposition of Aβ1-42 in the hippocampus and maintained the integrity of synaptic structures in the hippocampus. Furthermore, in the Morris water maze test, α7 nAChR improved the learning and memory ability of the APP/PS1_DT mice. CONCLUSION Theα7 nAChR attenuate the toxic effect of Aβ in vivo and in vitro, eg reduced the deposition of Aβ in the hippocampus,prevented the synaptic loss, partially restored the expression levels of synaptic-associated proteins, and improved the learning and memory abilities of APP/PS1_DT mice. Our results also suggested that the α7 nAChR interacted with Aβby mediated by Ca M-Ca MKⅡ-CREB signalling pathway, which was imbalanced by deposition of Aβ.展开更多
AIM: Review of evidence that the 33-amino-acidpolypeptide secretoneurin, which is generated byproteolytic cleavage of secretogranin Ⅱ, plays a role inneurogenic inflammation. METHODS: Survey of theliterature using a ...AIM: Review of evidence that the 33-amino-acidpolypeptide secretoneurin, which is generated byproteolytic cleavage of secretogranin Ⅱ, plays a role inneurogenic inflammation. METHODS: Survey of theliterature using a MEDLINE search database. RE-SULTS: Secretoneurin is synthesized in spinalganglia, transported through the dorsal roots and storedin the axon terminals of primary afferent neurons.Investigations using capsaicin suggest that secretoneurinfunctions as an excitatory transmitter. Secretoneurinspecifically activates various cell functions including thechemotactic migration of monocytes, eosinophils,fibroblasts, smooth muscle cells, and endothelial cells,展开更多
文摘OBJECTIVE Alzheimer disease(AD) is the most common type of dementia and is featured by the accumulation of β-amyloid peptide(Aβ) in the brain. The Alpha 7 nicotinic acetylcholine receptor family(α7 nAChR) was widely considered to interact with that Aβ, mediate neuroprotection and improve cognitive performance. However, the mechanisms underlying these interactions remain elusive. The present study aimed to determine how this interaction contribute to AD pathology. METHODS In vitro model of AD(primary culture of mice hippocampus treated with Aβ) and in vivo, a mouse model of AD(APPswe/PSEN1 d E9 double transgenic mice, APP/PS1_DT mice) were used to study to the possible inter-action of α7 nAChR and Aβ in the pathogenesis of AD. In vitro experiments, the primary hippocampal neurons cell was exposed to Aβ1-42 peptides in combination with PNU. In vivo experiments, different drugs/operations was applied to APP/PS1_DT mice for setting up of the following groups: WP group, wild-type C57 mice treated with PNU(α7 nAChR specific agonist);AP group, APP/PS1_DT mice treated with PNU;APP/PS1 group, the APP/PS1_DT mice injected intraperitoneally with the same amount of normal saline for 5 d;Control group, wild-type C57 mice injected intraperitoneally with the same amount of normal saline for 5 d. A transmission electron microscope was used to observed the synaptic morphological changes of hippocampal neurons. Reverse transcription quantitative PCR(RT-q PCR) and Western blot analysis were used to detect the expression levels of synaptic-associated proteins(SYN, SNAP25 etc). The learning and memory abilities of mice were detected by Morris water maze. RESULTS In vitro, it was found that α7 nAChR acts as an anti-Aβ-induced synaptic injury to nerve cell by increased the expression of synaptic-associated proteins and attenuated apoptosis induced by Aβ oligomers. In vivo, α7 nAChR attenuated synaptic loss induced by Aβ1-42, reduced the deposition of Aβ1-42 in the hippocampus and maintained the integrity of synaptic structures in the hippocampus. Furthermore, in the Morris water maze test, α7 nAChR improved the learning and memory ability of the APP/PS1_DT mice. CONCLUSION Theα7 nAChR attenuate the toxic effect of Aβ in vivo and in vitro, eg reduced the deposition of Aβ in the hippocampus,prevented the synaptic loss, partially restored the expression levels of synaptic-associated proteins, and improved the learning and memory abilities of APP/PS1_DT mice. Our results also suggested that the α7 nAChR interacted with Aβby mediated by Ca M-Ca MKⅡ-CREB signalling pathway, which was imbalanced by deposition of Aβ.
基金Project supported in part by the Austrian Science Foundation grant № P-09977-Med to CJW.
文摘AIM: Review of evidence that the 33-amino-acidpolypeptide secretoneurin, which is generated byproteolytic cleavage of secretogranin Ⅱ, plays a role inneurogenic inflammation. METHODS: Survey of theliterature using a MEDLINE search database. RE-SULTS: Secretoneurin is synthesized in spinalganglia, transported through the dorsal roots and storedin the axon terminals of primary afferent neurons.Investigations using capsaicin suggest that secretoneurinfunctions as an excitatory transmitter. Secretoneurinspecifically activates various cell functions including thechemotactic migration of monocytes, eosinophils,fibroblasts, smooth muscle cells, and endothelial cells,
