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α-secretase ADAM IO physically interacts with β-secretase BACE1 in neurons and regulates CHL1 proteolysis

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Journal of Molecular Cell Biology 2018年第5期10卷 411-422页

作者： Xin Wang Congcong Wang Gang Pei State Key Laboratory of Cell Biology CAS Center for Excellence in Molecular Cell Science Shanghai Institute of Biochemistry and Cell Biology Chinese Academy of Sciences University of Chinese Academy of Sciences Shanghai 200031 China Shanghai Key Laboratory of Signaling and Disease Research Collaborative Innovation Center for Brain Science School of Life Sciences and Technology Tongji University Shanghai 200092 China

α-secretase and β-secretase are known to compete for amyloid precursor protein （APP） processing and thus play a vital role in Alzheimer＇s disease pathogenesis. A disintegrin and metaUoproteinase 10 （ADAM10） and β-site APP cleaving enzyme 1 （BACE1） mediate the major activities of α-secretase and β-secretase in brain and share various common substrates. However, whether they function separately or together is poorly understood. Here, we show that ADAM10 and BACE1 co-localize in the neurites of mouse primary neurons. Co-immunoprecipitation and fluorescence resonance energy transfer analysis revealed that ADAM10 and BACE1 interact with each other under both endogenous and exogenous conditions. In addition, we found that ADAMIO enhances the proteolysis of neural cell adhesion molecule close homolog of L1 （CHL1） by BACE1. Further studies found that ADAM10-BACE1 interaction interfering peptide LT52 attenuates the regulation of ADAM10 on BACEl-mediated cleavage of CHL1. Our data indicate that ADAM10-BACE1 interaction regulates the proteolysis of some specific substrates and may play a potential role in brain function.

关键词： secretase Alzheimer's disease ADAM10 BACE1 interact APP CHL1

Targeting β-secretase with RNAi in neural stem cells for Alzheimer's disease therapy

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Neural Regeneration Research 2013年第33期8卷 3095-3106页

作者： Zhonghua Liu Shengliang Li Zibin Liang Yan Zhao Yulin Zhang Yaqi Yang Minjuan Wang Feng Li Department of Neurobiology and Anatomy Zhongshan School of MedicineSun Yat-sen University

There are several major pathological changes in Alzheimer＇s disease, including apoptosis of cho- linergic neurons, overactivity or overexpression of 13-site amyloid precursor protein cleaving enzyme 1 （BACE1） and inflammation. In this study, we synthesized a 19-nt oligonucleotide targeting BACE1, the key enzyme in amyloid beta protein （AI3） production, and introduced it into the pSilenCircle vector to construct a short hairpin （shRNA） expression plasmid against the BACE1 gene. We transfected this vector into C17.2 neural stem cells and primary neural stem cells, resulting in downregulation of the BACE1 gene, which in turn induced a considerable reduction in reducing AI3 protein production. We anticipate that this technique combining cell transplantation and gene ther- apy will open up novel therapeutic avenues for Alzheimer＇s disease, particularly because it can be used to simultaneously target several pathogenetic changes in the disease.

关键词： neural regeneration neurodegenerative disease secretase neural stem cells Alzheimer'sdisease C17.2 neural stem cells primary neural stem cells shRNA plasmid genetic modification grants-supported paper neuroregeneration

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The cryo-electron microscopy structure of γ-secretase: towards complex assembly, substrate recognition and a catalytic mechanism

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National Science Review 2015年第1期2卷 4-5页

作者： Yanyong Kang Karsten Melcher H.Eric Xu Laboratory of Structural Sciences Van Andel Research Institute Shanghai Institute of Materia Medica Chinese Academy of Sciences

Alzheimer’s disease(AD)is the most common form of neurodegenerative disorder to cause dementia in the *** afects millions of people worldwide and puts tremendous emotional and economic burden on afected *** is estima... 详细信息

关键词： The cryo-electron microscopy structure of towards complex assembly substrate recognition and a catalytic mechanism secretase

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β-secretase与阿尔茨海默病药物

Acta Biochimica et Biophysica Sinica 2000年第2期 191-191页

作者：李潇

Down-regulation amyloid β-protein 42 production by interfering with transcript of presenilin 1 gene with siRNA

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Acta Pharmacologica Sinica 2004年第12期25卷 47-52页

作者： Huan-min LUO2, Hui DENG, Fei XIAO, Qin GAO, Wen WENG, Pei-fen ZHANG, Xiao-guang LI Neuropharmacological Research Laboratory, College ofPharmacy, Ji-nan University, Guangzhou 510632, China Neuropharmacological Research Laboratory College of Pharmacy Ji-nan University Guangzhou 510632 Chin

AIM: To investigate the pathogenesis of Aβ42yielding and new drug targets as well as the possibility of RNA interference (RNAi) technique for treatment of Alzheimer disease (AD). METHODS: Human AD presenilin 1 (PS1) cDNA sequence was obtained from NCBI website. The three sites of RNAi action and one missense control site were selected in PS1 cDNA through online design of Ambion company. To confirm specificity of these sites, we conducted a BLAST search of the IMAGE EST library. The corresponding double-stranded DNA was used to construct pSilencer 3.1-H1 plasmid, which could transcribe small interference RNA (siRNA). Then, the pSliencer 3.1-H1 plasmids were transfected into CHO/PS1/APP cells with SuperFect transfection reagent. The cells have been transfected with the mutant PS1 and APP gene of AD. All the CHO/PS1/APP cells with pSliencer 3.1-H1 plasmids were screened out using G418. Transcripts of PS1 gene in CHO/PS1/APP were measured by RT-PCR, the contents of PS1 peptide and Aβ42 production inside CHO/PS1/APP cells were examined through Western blot and the Aβ42 change of secretion by CHO/PS1/APP was determined with ELISA. RESULTS: The site 3 of PS1 mRNA was inhibited by RNAi after 2 d. The effect was more obvious with the time. The peptide corresponding to PS1 gene and Aβ42 production in CHO/PS1/APP cells were both reduced after siRNA interfere for 3 d. Aβ42 secretion by CHO/PS1/APP cells began to reduce on d 3, and reached the most significance on d 5. There was a time-dependent relationship between the transcript of PS1 gene and the production of Aβ42with RNAi action. CONCLUSION: PS1 is essential for γ-secretase activity. Inhibition of the PS1 can decrease the levels of Aβ42. Some sites of PS1 mRNA, for example, the site 3, may serve as a new drug target and RNAi probably can be used for treatment of AD.

关键词： amyloid beta-protein amyloid beta-protein precursor secretase presenilin-1 RNA interference small-interfering RNA Alzheimer disease

Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs

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Translational Neurodegeneration 2016年第1期5卷 107-117页

作者： Riqiang Yan Department of Neurosciences Lerner Research InstituteCleveland Clinic Foundation9500 Euclid Avenue/NC30ClevelandOH 44195USA

Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily *** the etiology of AD remains an enigma,excessive accumulation ofβ-amyloid peptide(Aβ)is widely believed to induce pathological changes and cause dementia in brains of AD ***1 was discovered to initiate the cleavage of amyloid precursor protein(APP)at theβ-secretase *** after this cleavage doesγ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ.Hence,blocking BACE1 proteolytic activity will suppress Aβ*** to the linkage of Aβto the potential cause of AD,extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD *** the recent breakthrough in developing brain-penetrable BACE1 inhibitors,targeting amyloid deposition-mediated pathology for AD therapy has now become more *** review will summarize various strategies that have successfully led to the discovery of BACE1 drugs,such as MK8931,AZD-3293,JNJ-54861911,E2609 and *** drugs are currently in clinical trials and their updated states will be *** the promise of reducing Aβgeneration and deposition with no alarming safety concerns,the amyloid cascade hypothesis in AD therapy may finally become validated.

关键词： Alzheimer’s disease Amyloid plaques Amyloid precursor protein secretase BACE1 Aspartyl protease Drug discovery Clinical trials Amyloid deposition β-amyloid peptide Fragment based drug discovery Verubecestat

Notoginseng Saponin Rg1 Prevents Cognitive Impairment through Modulating APP Processing in Aβ1-42-injected Rats

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Current Medical Science 2019年第2期39卷 196-203页

作者： Shang-zhi LIU Wei CHENG Jia-wei SHAO Yun-fan GU Yi-yi ZHU Qi-jing DONG Si-yu BAI Ping WANG Li LIN Cell Molecular Biology Laboratory of Basic Medical College Hubei University of Chinese MedicineWuhan 430065China Hubei Research Institute of Geriatrics Collaborative Innovation Center of Hubei ProvinceHubei University of Chinese MedicineWuhan 430065China

With the intensification of the aging process of the world,Alzheimer's disease(AD),which is the main type of senile dementia,has become a primary problem in the present *** of strategies have been used to prevent and treat AD in animal nlodels and clinical trials,but most of them ended in *** notoginseng saponins(PNS)contain a variety of monomer compositions which have been separated and *** of the monomer compositions,notoginseng saponin Rg1(Rg1)accounts for 20%of the cultivation of panax notoginseng *** now PNS have been reported to be widely used to treat cardicerebrovascular diseases and have neuroprotective effects to restrain theβ-amyloid peptide(Aβ)25-35-niediated ***,it is reported that PNS could accelerate the growth of nerve cells,increase the length of axons and promote synaptic *** Rg1 can ameliorate the cognitive impairment and the underlying mechanism has not been *** study the preventive effect of Rg1 on cognitive impairment and the possible mechanism,we established the cognitive impairment model in rats through Aβ1-42(2.6μg/μL,5μL)injection and then treated the rats with Rg1(25,50 and 100 mg/kg)administered intragastrically for 4 *** observed that Aβ1-42 could induce spatial learning and memory deficits in ***,Aβ1-42 injection also resulted in the reduced neuron number in comuammonis 1(CA1)and dentate gyrus(DG)of hippocampus,as well as the increased level of hyperphosphorylatedβ-amyloid precursor protein(APP)at Thr668 site with up-regulation ofβ-APP cleaving enzyme 1(BACE1)and presenilin 1(PS1)and down-regulation of a disintegrin and metalloprotease domain-containing protein 10(ADAM 10)and insulindegrading enzyme(IDE).Administration of Rg1 effectively rescued the cognitive impairment and neuronal loss,and inhibited theβ-secretase processing of APP through reducing APP-Thr668 phosphorylation and BACE1/PS1 expression,and increasing the expression of ADAM

关键词： notoginseng saponin Rg1 Alzheimer's disease spatial learning and memory deficits β-amyloid peptide secretase degrading cnzyme

Role of BACE1 in Alzheimer’s synaptic function

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Translational Neurodegeneration 2017年第1期6卷 217-224页

作者： Brati Das Riqiang Yan Department of Neurosciences Lerner Research InstituteCleveland Clinic9500 Euclid Avenue/NC30ClevelandOH 44195USA

Alzheimer’s disease(AD)is the most common age-dependent disease of dementia,and there is currently no cure *** hallmark pathologies of AD are the presence of amyloid plaques and neurofibrillary *** the exact etiology of AD remains a mystery,studies over the past 30 have shown that abnormal generation or accumulation of β-amyloid peptides(Aβ)is likely to be a predominant early event in AD pathological development.Aβ is generated from amyloid precursor protein(APP)via proteolytic cleavage by β-site APP cleaving enzyme 1(BACE1).Chemical inhibition of BACE1 has been shown to reduce Aβ in animal studies and in human *** BACE1 inhibitors are currently being tested in clinical trials to treat AD patients,it is highly important to understand whether BACE1 inhibition will significantly impact cognitive functions in AD *** review summarizes the recent studies on BACE1 synaptic *** knowledge will help to guide the proper use of BACE1 inhibitors in AD therapy.

关键词： Amyloid deposition β-amyloid peptide BACE1 secretase BACE1 substrates Synaptic functions

Novel aspects of the apolipoprotein-E receptor family： regulation and functional role of their proteolytic processing

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Frontiers in Biology 2012年第2期7卷 113-143页

作者： Jorge A. LARIOS Maria-Paz MARZOLO Laboratorio de Trafico lntracelular y Senalizacion Departamento de Biologla Celular y Molecular Pontifieia Universidad Catolica de Chile Alameda # 340 Santiago Chile Millenium Nucleus in Regenerative Biology （MINREB） Facultad de Ciencias Biol6gieas Pontificia Universidad Catolica de Chile Alameda # 340 Santiago Chile

Studies related to the functional and regulatory aspects of proteolytic processing are of interest to cell biologists, developmental biologists and investigators who work on human diseases. Much of what is known about this topic derives from the study of the proteolytic processing of the amyloid precursor protein （APP）, which is involved in the pathology of Alzheimer＇s disease, and of the Notch protein and its Delta ligand, which play roles during embryonic development and in biologic processes in the adult. The proteolytic processing of plasma membrane receptor proteins is under the control of different enzymes that are responsible for releasing the ectodomain into the extracellular environment, where it has the potential to function as a signaling molecule and/or regulate the availability of the receptor＇s ligand. Following shedding of the ectodomain, the y-secretase enzymatic complex cleaves the transmembrane domain and releases the cytoplasmic domain （ICD） of the receptor. The ICD can function in the cytoplasm and/or at the nucleus. Members of the low-density lipoprotein receptor （LDLR） family are cndocytic-signaling proteins that perform a wide variety of physiologic functions during development and in the adult life. In addition these receptors have been implicated in a variety of diseases in adults. The prototypic receptor for this family of proteins is the LDLR itself. Besides their binding to apolipoproteins, these receptors bind many ligands that are destined for internalization and degradation. Some ligands have signaling properties. The proteolytic processing of certain members of the LDLR family not only controls receptor availability at the cell surface but also has functional consequences that amplify the spectrum of roles that these receptors perform. In addition, many complex regulatory mechanisms control the proteolytie processing of these receptors.

关键词： ADAM APP LDLR LRP metalloproteinase secretase