Amyloid-β<sub>42</sub> (Aβ<sub>42</sub>) accumulates within senileplaque, a pathological hall mark of Alzheimer’s disease (AD). Our previous reports showed that the monoclonal antibodies 37-...Amyloid-β<sub>42</sub> (Aβ<sub>42</sub>) accumulates within senileplaque, a pathological hall mark of Alzheimer’s disease (AD). Our previous reports showed that the monoclonal antibodies 37-11 and 77-3 react with conformational epitopes on the surface of the soluble aggregates of Aβ<sub>42</sub> and that sandwich ELISA using these two monoclonal antibodies yields high reactivity to detect soluble aggregates of Aβ<sub>42</sub>. Here, the reactivity of the sandwich ELISA was shown to increase in the presence of 50 μM Cu<sup>2+</sup>. However, the addition of Cu<sup>2+</sup> had only a small effect on the reactivity of a direct ELISA using antibody 37-11 or 77-3, suggesting that Cu<sup>2+</sup> has a small effect on the number of epitopes on the surface of the aggregates. Atomic force microscopy images showed that larger aggregates were formed in the presence of Cu<sup>2+</sup>, as shown in the other reports. Cu<sup>2+</sup> may gather the aggregates with distinct epitopes recognized by antibodies 37-11 and 77-3, leading to increased signal intensity of the sandwich ELISA.展开更多
The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a smal...The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer＇s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.展开更多
Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, bu...Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.展开更多
文摘Amyloid-β<sub>42</sub> (Aβ<sub>42</sub>) accumulates within senileplaque, a pathological hall mark of Alzheimer’s disease (AD). Our previous reports showed that the monoclonal antibodies 37-11 and 77-3 react with conformational epitopes on the surface of the soluble aggregates of Aβ<sub>42</sub> and that sandwich ELISA using these two monoclonal antibodies yields high reactivity to detect soluble aggregates of Aβ<sub>42</sub>. Here, the reactivity of the sandwich ELISA was shown to increase in the presence of 50 μM Cu<sup>2+</sup>. However, the addition of Cu<sup>2+</sup> had only a small effect on the reactivity of a direct ELISA using antibody 37-11 or 77-3, suggesting that Cu<sup>2+</sup> has a small effect on the number of epitopes on the surface of the aggregates. Atomic force microscopy images showed that larger aggregates were formed in the presence of Cu<sup>2+</sup>, as shown in the other reports. Cu<sup>2+</sup> may gather the aggregates with distinct epitopes recognized by antibodies 37-11 and 77-3, leading to increased signal intensity of the sandwich ELISA.
文摘The most prevalent form of dementia in the elderly is Alzheimer＇s disease.A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-β42（Aβ42）,a small hydrophobic peptide.Unfortunately,attempts to develop therapies targeting the accumulation of Aβ42 have not been successful to treat or even slow down the disease.It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach.The accumulation of Aβ42 seems to affect various aspects of physiological cell functions.In this review,we provide an overview of the evidence that implicates Aβ42 in synaptic dysfunction,with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release.We discuss data that provide new insights on the Aβ42 induced pathology of Alzheimer＇s disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease.Although the precise mechanisms that trigger synaptic dysfunction are still under investigation,the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention.
基金supported by the National Natural Science Foundation of China,No.81171191(to LYZ)the Shenzhen Special Fund Project on Strategic Emerging Industry Development of China,No.JCYJ20160422170522075(to LYZ)the Shenzhen Healthcare Research Project of China,No.201601015(to LYZ)
文摘Optogenetics is a combination of optics and genetics technology that can be used to activate or inhibit specific cells in tissues. It has been used to treat Parkinson’s disease, epilepsy and neurological diseases, but rarely Alzheimer’s disease. Adeno-associated virus carrying the CaMK promoter driving the optogenetic channelrhodopsin-2 (CHR2) gene (or without the CHR2 gene, as control) was injected into the bilateral dentate gyri, followed by repeated intrahippocampal injections of soluble low-molecular-weight amyloid-β1–42 peptide (Aβ1–42). Subsequently, the region was stimulated with a 473 nm laser (1–3 ms, 10 Hz, 5 minutes). The novel object recognition test was conducted to test memory function in mice. Immunohistochemical staining was performed to analyze the numbers of NeuN and synapsin Ia/b-positive cells in the hippocampus. Western blot assay was carried out to analyze the expression levels of glial fibrillary acidic protein, NeuN, synapsin Ia/b, metabotropic glutamate receptor-1a (mGluR-1a), mGluR-5, N-methyl-D-aspartate receptor subunit NR1, glutamate receptor 2, interleukin-1β, interleukin-6 and interleukin-10. Optogenetic stimulation improved working and short-term memory in mice with Alzheimer’s disease. This neuroprotective effect was associated with increased expression of NR1, glutamate receptor 2 and mGluR-5 in the hippocampus, and decreased expression of glial fibrillary acidic protein and interleukin-6. Our results show that optogenetics can be used to regulate the neuronal-glial network to ameliorate memory functions in mice with Alzheimer’s disease. The study was approved by the Animal Resources Committee of Jinan University, China (approval No. LL-KT-2011134) on February 28, 2011.
