Studies of amyloid precursor protein trafficking and processing

Alzheimer’s disease (AD) is the most common form of neurodegenerative disease that slowly impairs memory and thinking abilities. Abnormal accumulation and aggregation of amyloid β peptides (Aβ), derived from proteolytic cleavage of the amyloid precursor protein (APP), is thought to be one of the critical triggers in the pathogenesis. The trafficking and processing of APP is a complex process which can be regulated by many proteins. This thesis aims to expand our understanding of mechanisms that regulate processing and trafficking of APP. Study I aims to characterize the synaptic distribution of APP. We found that under normal conditions APP primarily distributed as fragments at synapses. Deletion of BACE1 led to an accumulation of APP C-terminal epitopes at synapses where APP N-terminal epitopes are present. A similar co-localization between APP N-terminals and C-terminals was also induced by pharmacological BACE1 inhibition. Moreover, proximity ligation assay revealed that the accumulation of APP C-terminals occurred in the presynaptic compartment. These results suggest that APP is primarily delivered to synapses as cleaved fragments, while full-length APP can be transported to the presynaptic compartment under conditions of reduced BACE1 activity. Study II aims to evaluate mechanisms for how exercise and BDNF regulate α-cleavage of APP. It has been suggested that regular exercise can reduce Aβ production. Moreover, exercise was suggested to enhance cognitive capacity, in which BDNF may contribute. We found that while the production of Aβ was reduced, the levels of sAPPα and BDNF were increased by exercise in a transgenic AD mouse model. Moreover, BDNF treatment was found to reduce Aβ production by regulating α-secretase activity. These results suggest that exercise and BDNF reduce Aβ production by enhancing α-secretase processing of APP. Study III and IV involve two members from the protein family of sorting nexins (SNXs), which have diverse functions in protein sorting and trafficking. Study III aims to elucidate the role of SNX3 in APP trafficking and processing as well as in Aβ production. In this study, the expression of SNX3 was manipulated by overexpression. We found that overexpression of SNX3 reduced the formation of Aβ. Moreover, SNX3 overexpression disturbed the association between APP and BACE1, and reduced APP internalization. While no change in BACE1 levels was found, APP levels were significantly decreased by SNX3 overexpression. These results suggest that overexpression of SNX3 decreases Aβ production by reducing internalization of APP. Study IV aims to test the involvement of SNX7 in Aβ production and APP processing. We found that overexpression of SNX7 decreased the levels of APP derived fragments, including Aβ. The cell surface and steady-state levels of APP, but not BACE1 were decreased by SNX7 overexpression. Moreover, the reduction of steady-state levels of APP was prevented by lysosomal inhibitors. Taken together, these results suggest that overexpression of SNX7 reduces Aβ production by enhancing lysosomal degradation of APP. In summary, we have examined mechanisms that regulate APP trafficking and processing, which may help develop novel therapeutic strategies for AD

A Normalized Fuzzy Neural Network and its Application

A normal fuzzy neural network(NFNN) with five layers is proposed. Focusing on the structure optimization of network, a new node selection method and corresponding back propagation learning algorithm rules are presented In the case with fewer input nodes, the training is more fast in this kind of neural network. Water-flooded zone identification in measure-well explanation is an important problem in the oil field development; especially in its later period. Complex geology conditions lead to many fuzzy characters in measure-well curves. In the combination of all kinds of fuzzy conditions, oil water-flooded behaves as strong water-flooded, middle water-flooded, weak water-flooded and no water-flooded, etc. NFNN is applied to water-flooded identification in oil well measure-well to find its mapping relation between well measure-well and water-flooded level,accordingly realize the water-flooded zone identification in measure-well explanation of fuzzy oil. Test results illustrate its practicabilit

Determining appropriate government guarantees for concession contract: lessons learned from 10 PPP projects in China

Governments worldwide are keen to encourage PPP schemes, however PPP is not a foolproof business. Many local governments and private investors have suffered severe or trying experiences. In this research, 10 case studies were conducted to identify the obstacles and difficulties for successful implementation of PPP projects from the perspective of government guarantees. These PPP projects include two water supply plants, two sewage treatment plants, two power supply plants, two highway projects, and two bridge projects. The findings obtained indicate that the local governments are familiar with “the type of guarantees” to provide to the private investor but they are unsure of the “amount” that should be given. Many PPP projects have therefore been heavily criticized for over benefiting the private investors as the government provides them with too many guarantees. The inappropriate guarantees offered by the government are regarded as one of the root causes of PPP projects’ failure. The lessons learned are valuable for determining appropriate government guarantees for future PPP projects and broadening the opportunities for infrastructure development with PPP procurement model

Discussion on course design of “Programming and Problem Solving” based on OBE-CDIO

Based on the OBE-CDIO model, this paper discusses how to design the course to achieve the goal of students’ ability training by taking the course “Programming and problem Solving” as an example. On the basis of analyzing the curriculum objectives and students’ needs, the student-centered teaching mode is realized through the research of course content design, teaching method selection and engineering case development. Through the questionnaire survey of the students in the course, some experience about this course is gained, and further research directions are proposed