ABSTRACT
The progressive aggregation of Amyloid-ß (Aß) in the brain is a major trait of Alzheimer's Disease (AD). Aß is produced as a result of proteolytic processing of the ß-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPß, Aß40, and Aß42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aß40 production over Aß42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPß production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the "regulatory landscape" of APP.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Protein Precursor/metabolism , Genetic Techniques , Metabolic Networks and Pathways , RNA, Small Interfering/analysis , Amyloid beta-Peptides/metabolism , Cell Survival , Diabetes Mellitus, Type 2/metabolism , Genome-Wide Association Study , Humans , Peptide Fragments/metabolism , Protein Processing, Post-Translational , Proteolysis , Serum Amyloid A Protein/metabolismABSTRACT
Objective: To observe the effect of Liuwei Dihuang decoction on brain development of intrauterine growth retardation rats,and to demonstrate the relationship between brain and kidney in TCM.Methods: Animals were divided into 4 groups at random: normal group,model group,Huangqi(HQ) and Liuwei Dihuang(LD) treated groups.The IUGR model was established by passive smoking.On the 19th day of pregnancy,all rats were killed;the total numbers of embryos,the lively,dead and absorbed embryos were counted.The body and brain weight of lively embryos were scaled respectively,then microstructure and apoptosis in brain were observed.Results: Passive smoking can result in the number of dead and absorbed embryos increases.Compared with normal group,the number of apoptotic cells of model group increased.Compared with model group,in Huangqi and Liuwei Dihuang treated groups,the number of dead and absorbed embryos decreased apparently,body and brain weight increased obviously,the number of apoptotic cells reduced significantly(P
