BACE

Summary

Gene Symbol: BACE
Description: beta-secretase 1
Alias: ASP2, BACE, HSPC104, beta-secretase 1, APP beta-secretase, asp 2, aspartyl protease 2, beta-secretase 1 precursor variant 1, beta-site APP cleaving enzyme 1, beta-site APP-cleaving enzyme, beta-site amyloid beta A4 precursor protein-cleaving enzyme, memapsin-2, membrane-associated aspartic protease 2, transmembrane aspartic proteinase Asp2
Species: human

Top Publications

  1. ncbi Determination of the active site protonation state of beta-secretase from molecular dynamics simulation and docking experiment: implications for structure-based inhibitor design
    Hwangseo Park
    School of Chemistry and Molecular Engineering, and Center for Molecular Catalysis, Seoul National University, Seoul 151 747, South Korea
    J Am Chem Soc 125:16416-22. 2003
  2. ncbi Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases
    Kristina Endres
    Institute of Biochemistry, Johannes Gutenberg University Mainz, Germany
    FEBS J 272:5808-20. 2005
  3. ncbi Selective inhibition of prenylated flavonoids from Sophora flavescens against BACE1 and cholinesterases
    Hyun Ah Jung
    Division of Food Science and Biotechnology, Pukyong National University, Busan, Republic of Korea
    Am J Chin Med 38:415-29. 2010
  4. pmc Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects
    Robert Vassar
    Department of Cell and Molecular Biology, Feinberg University School of Medicine, Northwestern University, Chicago, Illinois, USA
    J Neurochem 130:4-28. 2014
  5. ncbi Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1
    Qiming Li
    Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 9111, USA
    J Biol Chem 279:10542-50. 2004
  6. ncbi GGA proteins mediate the recycling pathway of memapsin 2 (BACE)
    Xiangyuan He
    Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, USA
    J Biol Chem 280:11696-703. 2005
  7. ncbi GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network
    Tina Wahle
    Department of Neurology, Laboratory of Molecular Cell Biology, University of Bonn, Sigmund Freud Str 25, 53127 Bonn, Germany
    Mol Cell Neurosci 29:453-61. 2005
  8. ncbi Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase
    Peer Hendrik Kuhn
    Adolf Butenandt Institut, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
    J Biol Chem 282:11982-95. 2007
  9. ncbi Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
    R Vassar
    Amgen, Inc, One Amgen Center Drive, M S 29 2 B, Thousand Oaks, CA 91320 1799, USA
    Science 286:735-41. 1999
  10. ncbi Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity
    R Yan
    Cell and Molecular Biology, Pharmacia and Upjohn, Inc, Kalamazoo, MI 49007, USA
    Nature 402:533-7. 1999

Research Grants

  1. Multiple Protein Structures in Computational Drug Design
    Heather A Carlson; Fiscal Year: 2013
  2. Yong Shen; Fiscal Year: 2014
  3. MiR-15/107 microRNAs are important genetic regulators in Alzheimer disease
    Peter T Nelson; Fiscal Year: 2012
  4. Peter T Nelson; Fiscal Year: 2016
  5. Non-amyloidogenic processing of APP
    Ruben Vidal; Fiscal Year: 2012
  6. Giuseppina Tesco; Fiscal Year: 2015
  7. Alzheimers Disease Mechanism & Experimental Therapeutic
    Philip Wong; Fiscal Year: 2009
  8. Casey J Brown; Fiscal Year: 2014
  9. Novel PET imaging agents for early diagnosis of plaque deposition in Alzheimer's
    Padmakar Kulkarni; Fiscal Year: 2010
  10. Zhongcong Xie; Fiscal Year: 2016

Detail Information

Publications226 found, 100 shown here

  1. ncbi Determination of the active site protonation state of beta-secretase from molecular dynamics simulation and docking experiment: implications for structure-based inhibitor design
    Hwangseo Park
    School of Chemistry and Molecular Engineering, and Center for Molecular Catalysis, Seoul National University, Seoul 151 747, South Korea
    J Am Chem Soc 125:16416-22. 2003
    b>Memapsin 2 (BACE) is an aspartyl protease known as beta-secretase that acts on the production of the beta-amyloid peptide in the human brain, a key event in the pathogenesis of Alzheimer's disease...
  2. ncbi Shedding of the amyloid precursor protein-like protein APLP2 by disintegrin-metalloproteinases
    Kristina Endres
    Institute of Biochemistry, Johannes Gutenberg University Mainz, Germany
    FEBS J 272:5808-20. 2005
    ..Retinoic acid treatment of two neuroblastoma cell lines upregulated the expression of both APLP2 and ADAM10, thus leading to an increased release of soluble APLP2...
  3. ncbi Selective inhibition of prenylated flavonoids from Sophora flavescens against BACE1 and cholinesterases
    Hyun Ah Jung
    Division of Food Science and Biotechnology, Pukyong National University, Busan, Republic of Korea
    Am J Chin Med 38:415-29. 2010
    ..Therefore, S. flavescens and its prenylated flavonoids, possessing low molecular weights and lipophilic moieties may be potent preventive and therapeutic candidates for Alzheimer's disease...
  4. pmc Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects
    Robert Vassar
    Department of Cell and Molecular Biology, Feinberg University School of Medicine, Northwestern University, Chicago, Illinois, USA
    J Neurochem 130:4-28. 2014
    ..This review highlights the recent progress in understanding cell biology, substrates, and functions of BACE proteases and discusses the therapeutic options and potential mechanism-based liabilities, in particular for BACE ..
  5. ncbi Cleavage of amyloid-beta precursor protein and amyloid-beta precursor-like protein by BACE 1
    Qiming Li
    Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390 9111, USA
    J Biol Chem 279:10542-50. 2004
    Site-specific proteolysis of the amyloid-beta precursor protein (APP) by BACE 1 and gamma-secretase, a central event in Alzheimer disease, releases a large secreted extracellular fragment (called APP(S)), peptides of 40-43 residues ..
  6. ncbi GGA proteins mediate the recycling pathway of memapsin 2 (BACE)
    Xiangyuan He
    Protein Studies Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104, USA
    J Biol Chem 280:11696-703. 2005
    b>Memapsin 2 (BACE, beta-secretase) is a membrane-associated aspartic protease that initiates the hydrolysis of beta-amyloid precursor protein (APP) leading to the production of amyloid-beta (A beta) and the progression of Alzheimer disease...
  7. ncbi GGA proteins regulate retrograde transport of BACE1 from endosomes to the trans-Golgi network
    Tina Wahle
    Department of Neurology, Laboratory of Molecular Cell Biology, University of Bonn, Sigmund Freud Str 25, 53127 Bonn, Germany
    Mol Cell Neurosci 29:453-61. 2005
    ..Our data indicate that GGA proteins are not only involved in the sorting at the TGN but also mediate the retrograde transport of cargo proteins from endosomes to the TGN...
  8. ncbi Regulated intramembrane proteolysis of the interleukin-1 receptor II by alpha-, beta-, and gamma-secretase
    Peer Hendrik Kuhn
    Adolf Butenandt Institut, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany
    J Biol Chem 282:11982-95. 2007
    ..This study reveals a similar proteolytic processing of IL-1R2 and APP and may provide an explanation for the increased IL-1R2 secretion observed in AD...
  9. ncbi Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
    R Vassar
    Amgen, Inc, One Amgen Center Drive, M S 29 2 B, Thousand Oaks, CA 91320 1799, USA
    Science 286:735-41. 1999
    ..Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were ..
  10. ncbi Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity
    R Yan
    Cell and Molecular Biology, Pharmacia and Upjohn, Inc, Kalamazoo, MI 49007, USA
    Nature 402:533-7. 1999
    ..Here we identify a new membrane-bound aspartyl protease (Asp2) with beta-secretase activity. The Asp2 gene is expressed widely in brain and other tissues...
  11. ncbi Identification of a novel aspartic protease (Asp 2) as beta-secretase
    I Hussain
    Department of Neurosciences, SmithKline Beecham Pharmaceuticals, Harlow, Essex, United Kingdom
    Mol Cell Neurosci 14:419-27. 1999
    ..Here we report that Asp 2, a novel transmembrane aspartic protease, has the key activities expected of beta-secretase...
  12. pmc Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein
    X Lin
    Protein Studies Program, Oklahoma Medical Research Foundation, and Department of Biochemistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
    Proc Natl Acad Sci U S A 97:1456-60. 2000
    The cDNAs of two new human membrane-associated aspartic proteases, memapsin 1 and memapsin 2, have been cloned and sequenced...
  13. ncbi Expression analysis of BACE2 in brain and peripheral tissues
    B D Bennett
    Amgen, Inc, Thousand Oaks, California 91320 1799, USA
    J Biol Chem 275:20647-51. 2000
    Beta-site amyloid precursor protein cleaving enzyme (BACE) is a novel transmembrane aspartic protease that possesses all the known characteristics of the beta-secretase involved in Alzheimer's disease (Vassar, R., Bennett, B. D...
  14. ncbi Maturation and pro-peptide cleavage of beta-secretase
    A Capell
    Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
    J Biol Chem 275:30849-54. 2000
    Amyloid beta-peptide is generated by two sequential proteolytic cleavages mediated by beta-secretase (BACE) and gamma-secretase. BACE was recently identified as a membrane-associated aspartyl protease...
  15. ncbi Phosphorylation regulates intracellular trafficking of beta-secretase
    J Walter
    Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 44 Schillerstrasse, 80336 Munich, Germany
    J Biol Chem 276:14634-41. 2001
    beta-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid beta-peptide...
  16. ncbi Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases
    Fiona Gruninger-Leitch
    Hoffmann La Roche Ltd, Grenzacherstrasse 124, CNS Research, CH 4070 Basel, Switzerland
    J Biol Chem 277:4687-93. 2002
    The full-length and ectodomain forms of beta-site APP cleavage enzyme (BACE) have been cloned, expressed in Sf9 cells, and purified to homogeneity...
  17. ncbi Beta-secretase processing in the trans-Golgi network preferentially generates truncated amyloid species that accumulate in Alzheimer's disease brain
    Jason T Huse
    Department of Microbiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
    J Biol Chem 277:16278-84. 2002
    ..The beta-secretase enzyme beta-site amyloid precursor protein-cleaving enzyme (BACE) generates the N terminus of A beta by cleavage at either Asp(1) (beta-site) or Glu(11) (beta'-site), ultimately ..
  18. ncbi The carboxyl-terminus of BACE contains a sorting signal that regulates BACE trafficking but not the formation of total A(beta)
    Lucia Pastorino
    Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA
    Mol Cell Neurosci 19:175-85. 2002
    b>BACE (beta-site APP cleaving enzyme) has been recently proposed as the major aspartyl protease displaying beta secretase activity in neurons...
  19. ncbi Increased expression of the amyloid precursor beta-secretase in Alzheimer's disease
    R M Damian Holsinger
    Department of Pathology, Mental Health Research Institute, The University of Melbourne, Parkville, Victoria 3010, Australia
    Ann Neurol 51:783-6. 2002
    ..7-fold increase in protein expression of the beta-secretase enzyme BACE in the brain cortex of Alzheimer's disease patients as compared to age-matched controls...
  20. ncbi Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease
    Hiroaki Fukumoto
    Alzheimer Disease Research Unit, Center for Aging, Genetics, and Neurodegeneration, Massachusetts General Hospital East, Bldg 114, Room 2010, 114 16th Street, Charlestown, MA 02129, USA
    Arch Neurol 59:1381-9. 2002
    ..processing of APP that results in Abeta formation requires 2 enzymatic cleavage events, a gamma-secretase cleavage dependent on presenilin, and a beta-secretase cleavage by the aspartyl protease beta-site APP-cleaving enzyme (BACE).
  21. ncbi alpha- and beta-secretase: profound changes in Alzheimer's disease
    Susan J Tyler
    Molecular Neurobiology Unit, URCN Care of the Elderly University of Bristol, Bristol Royal Infirmary, Bristol, UK
    Biochem Biophys Res Commun 299:373-6. 2002
    ..Eighty percent of Alzheimer brains examined had an increase in beta-secretase, a decrease in alpha-secretase, or both; which may account for the means by which the majority of people develop Alzheimer's disease...
  22. ncbi Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease
    Li Bang Yang
    Nat Med 9:3-4. 2003
  23. ncbi Characterization of the ectodomain shedding of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1)
    Ishrut Hussain
    Neurology and Gastrointestinal Centre of Excellence for Drug Discovery, GlaxoSmithKline Research and Development Limited, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom
    J Biol Chem 278:36264-8. 2003
    ..In addition, we show that the BACE1 sheddase is distinct from alpha-secretase and, importantly, that inhibition of BACE1 shedding does not influence amyloid precursor protein processing at the beta-site...
  24. ncbi The cell adhesion protein P-selectin glycoprotein ligand-1 is a substrate for the aspartyl protease BACE1
    Stefan F Lichtenthaler
    Massachusetts General Hospital Harvard Medical School, Department of Molecular Biology, Boston, Massachusetts 02114, USA
    J Biol Chem 278:48713-9. 2003
    ..The cleavage occurred at a Leu-Ser peptide bond as identified by mass spectrometry using a synthetic peptide. We conclude that PSGL-1 is an additional substrate for BACE1...
  25. pmc Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer's disease patients
    Rena Li
    Haldeman Laboratory of Molecular and Cellular Neurobiology, L J Roberts Center for Alzheimer s Research, Sun Health Research Institute, Sun City, AZ 85351, USA
    Proc Natl Acad Sci U S A 101:3632-7. 2004
    Whether elevated beta-secretase (BACE) activity is related to plaque formation or amyloid beta peptide (Abeta) production in Alzheimer's disease (AD) brains remains inconclusive...
  26. ncbi BACE (beta-secretase) modulates the processing of APLP2 in vivo
    L Pastorino
    Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA
    Mol Cell Neurosci 25:642-9. 2004
    b>BACE is an aspartyl protease that cleaves the amyloid precursor protein (APP) at the beta-secretase cleavage site and is involved in Alzheimer's disease...
  27. ncbi Processing amyloid precursor protein at the beta-site requires proper orientation to be accessed by BACE1
    Isam Qahwash
    Cell and Molecular Biology, Protein Sciences, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA
    J Biol Chem 279:39010-6. 2004
    ....
  28. ncbi Human BACE forms dimers and colocalizes with APP
    Ariane Schmechel
    Freie Universitaet Berlin, Institut fuer Chemie Biochemie, Thielallee 63, Berlin D 14195, Germany
    J Biol Chem 279:39710-7. 2004
    Beta-site APP-cleaving enzyme (BACE) is a membrane-bound aspartyl protease with no strict primary preference for cleavage...
  29. ncbi Dimerization of beta-site beta-amyloid precursor protein-cleaving enzyme
    Gil G Westmeyer
    Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Schillerstrasse 44, Ludwig Maximilians University, 80336 Munich, Germany
    J Biol Chem 279:53205-12. 2004
    Cleavage of the beta-amyloid precursor protein (APP) by the aspartyl protease beta-site APP-cleaving enzyme (BACE) is the first step in the generation of the amyloid beta-peptide, which is deposited in the brain of Alzheimer's disease ..
  30. pmc BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions
    Fiona M Laird
    Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurosci 25:11693-709. 2005
    ....
  31. ncbi Reticulons RTN3 and RTN4-B/C interact with BACE1 and inhibit its ability to produce amyloid beta-protein
    Kiyoko S Murayama
    Department of Demyelinating Disease and Ageing, National Institute of Neuroscience, NCNP, 4 1 1 Ogawahigashi, Kodaira, Tokyo 187 8502, Japan
    Eur J Neurosci 24:1237-44. 2006
    ..Because RTN3 and RTN4-B/C are substantially expressed in neural tissues, our findings suggest that they play important roles in the regulation of BACE1 function and Abeta production in the brain...
  32. ncbi BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease
    Dione Kobayashi
    Rinat Neurosciences, 230 East Grand Avenue, South San Francisco, CA 94080, USA
    Neurobiol Aging 29:861-73. 2008
    ..These results suggest that while excess Abeta is functionally pathological, BACE1-mediated processing of APP and other substrates play a role in "normal" learning, memory and sensorimotor processes...
  33. ncbi Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis
    Jie Zhao
    Department of Cell and Molecular Biology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
    J Neurosci 27:3639-49. 2007
    ..To distinguish between these possibilities, we analyzed BACE1 elevation using a highly specific BACE1 antibody, BACE-Cat1, made in BACE1-/- mice, which mount a robust anti-BACE1 immune response...
  34. pmc A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1
    Claudio Costantini
    Department of Medicine, University of Madison Wisconsin, Madison, WI 53705, USA
    Biochem J 407:383-95. 2007
    ..Site-directed mutagenesis indicates that lysine acetylation is necessary for nascent BACE1 to leave the ER and move ahead in the secretory pathway, and for the molecular stabilization of the protein...
  35. doi A novel sorting nexin modulates endocytic trafficking and alpha-secretase cleavage of the amyloid precursor protein
    Susanne Schöbel
    Center for Integrated Protein Science and the Adolf Butenandt Institut, Ludwig Maximilians University, Munich, Germany
    J Biol Chem 283:14257-68. 2008
    ....
  36. doi Impact of cholesterol level upon APP and BACE proximity and APP cleavage
    Christine A F von Arnim
    Deparment of Neurology, Ulm University, Albert Einstein Allee 11, 89081 Ulm, Germany
    Biochem Biophys Res Commun 370:207-12. 2008
    Cleavage of APP by BACE is the first proteolytic step in the production of Amyloid beta (Abeta, which accumulates in senile plaques in Alzheimer's disease. BACE-cleavage of APP is thought to happen in endosomes...
  37. pmc Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production
    Hideaki Shimizu
    Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2 1 Hirosawa, Wako Shi, Saitama 351 0198, Japan
    Mol Cell Biol 28:3663-71. 2008
    ..These findings provide insight into a novel regulation of BACE1 activity and elucidate how BACE1 modulates its activity during cellular trafficking...
  38. pmc Expression of a noncoding RNA is elevated in Alzheimer's disease and drives rapid feed-forward regulation of beta-secretase
    Mohammad Ali Faghihi
    Molecular and Integrative Neurosciences Department, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA
    Nat Med 14:723-30. 2008
    ..In summary, we report that a long noncoding RNA is directly implicated in the increased abundance of Abeta 1-42 in Alzheimer's disease...
  39. pmc PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1
    Mary Cabell Jonas
    Department of Medicine, University of Wisconsin Madison, VAH GRECC 11G, 2500 Overlook Terrace, Madison, Wisconsin 53705, USA
    EMBO Rep 9:916-22. 2008
    ..In addition, Pcsk9(-/-) mice showed increased levels of BACE1 and Abeta in the brain. Finally, we found that nascent low-density lipoprotein receptor, a known substrate of PCSK9, is also acetylated...
  40. doi Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease
    Henrik Zetterberg
    Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at Goteborg University, Molndal, Sweden
    Arch Neurol 65:1102-7. 2008
    ....
  41. pmc Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels
    Mi Hee Ko
    Department of Medicine, University of Wisconsin Madison and Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin 53705, USA
    J Biol Chem 284:2482-92. 2009
    ..The biochemical characterization of the above events could lead to the identification of novel pharmacological strategies for the prevention of this form of dementia...
  42. doi Function, regulation and therapeutic properties of beta-secretase (BACE1)
    Michael Willem
    Center for Integrated Protein Science Munich, Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Neurodegenerative Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
    Semin Cell Dev Biol 20:175-82. 2009
    ..BACE1 is a primary target for Abeta lowering therapies, however the development of high affinity bio-available inhibitors has been a major challenge so far...
  43. pmc BACE1 and BACE2 enzymatic activities in Alzheimer's disease
    Rachel R Ahmed
    Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, USA
    J Neurochem 112:1045-53. 2010
    ..However, as both forms of BACE compete for the same substrate pool, even small changes in BACE2 activity could have consequences for human disease.
  44. pmc Identification of beta-secretase (BACE1) substrates using quantitative proteomics
    Matthew L Hemming
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 4:e8477. 2009
    ..These findings expand our understanding of the proteins and cellular processes that BACE1 may regulate, and suggest possible mechanisms of toxicity arising from chronic BACE1 inhibition...
  45. pmc Partial reduction of BACE1 improves synaptic plasticity, recent and remote memories in Alzheimer's disease transgenic mice
    Ryoichi Kimura
    Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, Orangeburg, New York 10962, USA
    J Neurochem 113:248-61. 2010
    ..5XFAD mice. Therefore, our findings provide compelling evidence for beneficial effects of partially BACE1-inhibiting approaches on multiple forms of functional defects associated with AD...
  46. doi BACE1 activity in cerebrospinal fluid and its relation to markers of AD pathology
    Sandra D Mulder
    Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands
    J Alzheimers Dis 20:253-60. 2010
    ..38, r=0.63, and r=0.65; all p< 0.05), but not with Abeta(42). These data suggest that increased BACE1 activity in CSF relates to AD pathology in the brain...
  47. pmc Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing
    Hirokazu Okada
    Integrated Program in Cellular, Molecular, and Biophysical Studies, Columbia University Medical Center, New York, New York, USA
    FASEB J 24:2783-94. 2010
    ..Our study identifies a novel cellular pathway by which SNX6 negatively modulates BACE1-mediated cleavage of APP...
  48. pmc Ubiquitin regulates GGA3-mediated degradation of BACE1
    Eugene L Kang
    Alzheimer s Disease Research Laboratory, Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA
    J Biol Chem 285:24108-19. 2010
    ..These findings indicate that levels of GGA3 tightly and inversely regulate BACE1 levels via interaction with ubiquitin sorting machinery...
  49. pmc Altered levels and distribution of amyloid precursor protein and its processing enzymes in Niemann-Pick type C1-deficient mouse brains
    A Kodam
    Department of Psychiatry, Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada
    Glia 58:1267-81. 2010
    ..These results, taken together, suggest that increased level and processing of APP may be associated with the development of pathology and/or degenerative events observed in Npc1(-/-) mouse brains...
  50. doi The role of low-density receptor-related protein 1 (LRP1) as a competitive substrate of the amyloid precursor protein (APP) for BACE1
    Bjoern von Einem
    Dept of Neurology, Ulm University, Albert Einstein Allee 11, 89081 Ulm, Germany
    Exp Neurol 225:85-93. 2010
    ..In conclusion, our data suggest that--in addition to its role in APP trafficking--LRP1 affects APP processing by competing for cleavage by BACE1...
  51. pmc β-Secretase-1 elevation in aged monkey and Alzheimer's disease human cerebral cortex occurs around the vasculature in partnership with multisystem axon terminal pathogenesis and β-amyloid accumulation
    Yan Cai
    Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, China
    Eur J Neurosci 32:1223-38. 2010
    ..The data provide a mechanistic explanation for why senile plaques are present preferentially near the cerebral vasculature...
  52. pmc Prion protein interacts with BACE1 protein and differentially regulates its activity toward wild type and Swedish mutant amyloid precursor protein
    Heledd H Griffiths
    Institute of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom
    J Biol Chem 286:33489-500. 2011
    ..Thus, although PrP(C) exerts no control on cleavage of APP(Swe) by BACE1, it has a profound influence on the cleavage of APP(WT), suggesting that PrP(C) may be a key protective player against sporadic Alzheimer disease...
  53. pmc ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1
    Ragna Sannerud
    Laboratory of Membrane Trafficking, Center for Human Genetics, Catholic University of Leuven, Leuven, Belgium
    Proc Natl Acad Sci U S A 108:E559-68. 2011
    ..It thereby provides a novel avenue to interfere with Aβ production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP...
  54. pmc Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination
    Viktorija Velanac
    Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Goettingen, Germany
    Glia 60:203-17. 2012
    ..Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing...
  55. doi Identification and biology of β-secretase
    Patty C Kandalepas
    Northwestern University, Feinberg School of Medicine, Department of Cell and Molecular Biology, 300 E Superior, Chicago, IL 60611, USA
    J Neurochem 120:55-61. 2012
    ..These data are crucial for predicting potential mechanism-based toxicity that would arise from inhibiting BACE1 for the treatment or prevention of AD...
  56. pmc β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1)-deficient mice exhibit a close homolog of L1 (CHL1) loss-of-function phenotype involving axon guidance defects
    Brian Hitt
    Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    J Biol Chem 287:38408-25. 2012
    ..Our results imply the possibility that axon mis-targeting may occur in adult neurogenic and/or regenerating neurons as a result of chronic BACE1 inhibition and add a note of caution to BACE1 inhibitor development...
  57. pmc BACE1 and presenilin/γ-secretase regulate proteolytic processing of KCNE1 and 2, auxiliary subunits of voltage-gated potassium channels
    Carolyn C Sachse
    Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    FASEB J 27:2458-67. 2013
    ..Our results also suggest a functional role of KCNE cleavage in regulating voltage-gated potassium channels...
  58. pmc The Alzheimer's β-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques
    Patty C Kandalepas
    Department of Cell and Molecular Biology, The Feinberg School of Medicine, Northwestern University, 300 East Superior Street, Tarry 8 713, Chicago, IL 60611 3006, USA
    Acta Neuropathol 126:329-52. 2013
    ..Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aβ generation and accelerate amyloid plaque growth in AD. ..
  59. pmc Targeting the β secretase BACE1 for Alzheimer's disease therapy
    Riqiang Yan
    Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    Lancet Neurol 13:319-29. 2014
    ..The potential of therapeutic BACE1 inhibition might prove to be a watershed in the treatment of Alzheimer's disease. ..
  60. ncbi BACE is degraded via the lysosomal pathway
    Young Ho Koh
    Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, 02129, USA
    J Biol Chem 280:32499-504. 2005
    ..A type I transmembrane aspartyl protease, BACE (beta-site APP cleaving enzyme), has been identified to be the beta-secretase...
  61. ncbi Purification and cloning of amyloid precursor protein beta-secretase from human brain
    S Sinha
    Elan Pharmaceuticals, South San Francisco, California 94080, USA
    Nature 402:537-40. 1999
    ..Cloning and expression of the enzyme reveals that human brain beta-secretase is a new membrane-bound aspartic proteinase...
  62. ncbi The BACE gene: genomic structure and candidate gene study in late-onset Alzheimer's disease
    T Murphy
    Department of Medical Genetics, Wellcome Trust Centre for Molecular Mechanisms in Disease, Cambridge Institute for Medical Research, UK
    Neuroreport 12:631-4. 2001
    ..Recently, the BACE gene, which encodes beta-secretase, the rate limiting enzyme in beta-amyloid formation, has been identified...
  63. ncbi The transmembrane domain of the Alzheimer's beta-secretase (BACE1) determines its late Golgi localization and access to beta -amyloid precursor protein (APP) substrate
    R Yan
    Department of Cell and Molecular Biology, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA
    J Biol Chem 276:36788-96. 2001
    ..beta-Secretase was recently identified as a novel membrane-bound aspartyl protease, named BACE1, Asp2, or memapsin 2. Employing confocal microscopy and subcellular fractionation, we have found that BACE1 is largely situated in ..
  64. ncbi Association study between Alzheimer's disease and genes involved in Abeta biosynthesis, aggregation and degradation: suggestive results with BACE1
    Jordi Clarimon
    Unitat de Biologia Evolutiva, Facultat de Ciencies de la Salut i de la Vida, Universitat Pompeu Fabra, Doctor Aiguader 80, 08003 Barcelona, Spain
    J Neurol 250:956-61. 2003
    ..of these processes: proteolytic cleavage of the amyloid precursor protein by the beta-site APP cleaving enzyme (BACE), increased amyloid fibril formation by the activity of the acetylcholinesterase (ACHE gene), and degradation of ..
  65. ncbi Insights into the phosphoregulation of beta-secretase sorting signal by the VHS domain of GGA1
    Tomoo Shiba
    Structural Biology Research Center, Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization KEK, Tsukuba, Ibaraki 305 0801, Japan
    Traffic 5:437-48. 2004
    b>BACE (beta-site amyloid precursor protein cleaving enzyme, beta-secretase) is a type-I membrane protein which functions as an aspartic protease in the production of beta-amyloid peptide, a causative agent of Alzheimer's disease...
  66. ncbi Reticulon family members modulate BACE1 activity and amyloid-beta peptide generation
    Wanxia He
    Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
    Nat Med 10:959-65. 2004
    ..Thus, changes in the expression of reticulon proteins in the human brain are likely to affect cellular amyloid-beta and the formation of amyloid plaques...
  67. ncbi Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy
    Christine A F von Arnim
    Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA
    J Cell Sci 117:5437-45. 2004
    beta-Secretase (BACE) carries out the first of two proteolysis steps to generate the amyloid-beta peptides that accumulate in the senile plaques in Alzheimer's disease (AD)...
  68. ncbi Biochemical and kinetic characterization of BACE1: investigation into the putative species-specificity for beta- and beta'-cleavage sites by human and murine BACE1
    Hsiu Chiung Yang
    Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA
    J Neurochem 91:1249-59. 2004
    ..It does not appear to be a significant species specificity to this cleavage...
  69. ncbi The low density lipoprotein receptor-related protein (LRP) is a novel beta-secretase (BACE1) substrate
    Christine A F von Arnim
    Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Biol Chem 280:17777-85. 2005
    b>BACE is a transmembrane protease with beta-secretase activity that cleaves the amyloid precursor protein (APP)...
  70. ncbi beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase
    Hon Kit Wong
    Laboratories for Structural Neuropathology, RIKEN Brain Science Institute, Saitama, Japan
    J Biol Chem 280:23009-17. 2005
    ..These results may provide new insights into the underlying pathology of Alzheimer disease...
  71. ncbi Screening a series of sialyltransferases for possible BACE1 substrates
    Shinobu Kitazume
    Glyco chain Functions Laboratory, Supra biomolecular System Group, Frontier Research System, RIKEN, 2 1 Hirosawa, Wako Shi, Saitama 351 0198, Japan
    Glycoconj J 23:437-41. 2006
    ..These results suggest that BACE1 expression affects glycosylation not only by directly cleaving glycosyltransferases but also by modifying the secretion of glycosyltransferases via some other mechanisms...
  72. pmc BACE1 regulates voltage-gated sodium channels and neuronal activity
    Doo Yeon Kim
    Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    Nat Cell Biol 9:755-64. 2007
    ..BACE1, by cleaving beta2, thus regulates Na(v)1 alpha-subunit levels and controls cell-surface sodium current densities. BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity...
  73. doi Identification of a cis-acting element involved in the regulation of BACE1 mRNA alternative splicing
    Karen R Mowrer
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    J Neurochem 109:1008-16. 2009
    ..Therefore, we have for the first time found evidence of a regulatory site involved in BACE1 alternative splicing, and these data indicate that minor sequence changes can dramatically alter BACE1 alternative splicing...
  74. doi Accumulation of insoluble amyloid-β in down's syndrome is associated with increased BACE-1 and neprilysin activities
    James Scott Miners
    Dementia Research Group, Institute of Clinical Neurosciences, University of Bristol, Bristol, UK
    J Alzheimers Dis 23:101-8. 2011
    We previously reported age- and Alzheimer's disease (AD)-related increases in the activities of β-secretase (BACE-1) and Aβ-degrading enzymes including neprilysin (NEP) and angiotensin-converting enzyme (ACE) in the frontal cortex...
  75. ncbi Polymorphism in the BACE gene influences the risk for Alzheimer's disease
    Chartika M Kirschling
    Department of Psychiatry, University of Bonn, Germany
    Neuroreport 14:1243-6. 2003
    ..Abeta is generated by cleavage of the amyloid precursor protein by beta- and gamma-secretases. BACE (beta-site APP cleaving enzyme) was identified as the beta-secretase...
  76. doi Binding of beta-secretase to a peptide inhibitor-carrying SAM
    Hiromi Kitano
    Department of Applied Chemistry, Graduate School of Science and Engineering, University of Toyama, Gofuku 3190, Toyama 930 8555, Japan
    Colloids Surf B Biointerfaces 78:155-62. 2010
    ..The results suggested that the SAM of the enzyme inhibitor can be used for both investigation of enzymes and removal of target enzymes from biological fluids...
  77. pmc beta-Secretase inhibitor potency is decreased by aberrant beta-cleavage location of the "Swedish mutant" amyloid precursor protein
    Hidekuni Yamakawa
    From the Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, Meguro ku, Tokyo 153 8902, Japan
    J Biol Chem 285:1634-42. 2010
    ..This work provides novel insights into the potency decrease of BSI and valuable suggestions for its development as a disease-modifying agent...
  78. ncbi BACE2 functions as an alternative alpha-secretase in cells
    R Yan
    Department of Cell and Molecular Biology, Pharmacia Corporation, Kalamazoo, Michigan 49007, USA
    J Biol Chem 276:34019-27. 2001
    ..Thus, BACE2 can be distinguished from BACE1 on the basis of autoprocessing of the prosegment, APP processing specificity, and subcellular localization patterns...
  79. doi Engineered heparins: novel beta-secretase inhibitors as potential Alzheimer's disease therapeutics
    S J Patey
    School of Biological Sciences, University of Liverpool, Liverpool, UK
    Neurodegener Dis 5:197-9. 2008
    ....
  80. doi Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors
    Michael S Malamas
    Department of Chemical Sciences, Wyeth Research, CN 8000, Princeton, New Jersey 08543 8000, USA
    J Med Chem 53:1146-58. 2010
    ..Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001)...
  81. ncbi Novel mutations introduced at the beta-site of amyloid beta protein precursor enhance the production of amyloid beta peptide by BACE1 in vitro and in cells
    Xiao Ping Shi
    Department of Biological Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    J Alzheimers Dis 7:139-48; discussion 173-80. 2005
    ..A BACE inhibitor blocked the processing of the APP_NFEV beta-site in vitro and in cells...
  82. pmc Alteration of BACE1-dependent NRG1/ErbB4 signaling and schizophrenia-like phenotypes in BACE1-null mice
    A V Savonenko
    Departments of Pathology, Neurology, and Neuroscience, Johns Hopkins University School of Medicine, 558 Ross Research Building, 720 Rutland Avenue, Baltimore, MD 21205, USA
    Proc Natl Acad Sci U S A 105:5585-90. 2008
    ..Collectively, our findings suggest that alterations in BACE1-dependent NRG1/ErbB4 signaling may participate in the pathogenesis of schizophrenia and related psychiatric disorders...
  83. ncbi Development and characterization of beta-secretase monolithic micro-immobilized enzyme reactor for on-line high-performance liquid chromatography studies
    Francesca Mancini
    Department of Pharmaceutical Sciences, Via Belmeloro 6, University of Bologna, 40126 Bologna, Italy
    J Chromatogr A 1175:217-26. 2007
    beta-Site APP cleavage enzyme 1 (BACE-1) is a transmembrane aspartyl protease that cleaves the amyloid-beta precursor protein (APP), which is abundant in neurons...
  84. ncbi BACE1 gene expression and protein degradation
    Weihui Zhou
    Department of Psychiatry, Brain Research Center, University of British Columbia, Vancouver, Canada
    Ann N Y Acad Sci 1035:49-67. 2004
    ..Furthermore, we found that BACE1 protein is ubiquitinated, and the degradation of BACE1 proteins and amyloid precursor protein processing are regulated by the ubiquitin-proteasome pathway...
  85. ncbi The role of APP processing and trafficking pathways in the formation of amyloid beta-protein
    D J Selkoe
    Centre for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Ann N Y Acad Sci 777:57-64. 1996
    ..In conclusion, studies of the regulation of A beta production and aggregation in cell culture can provide information under physiological conditions that can complement analyses of these processes in vivo...
  86. ncbi GEPT extract reduces Abeta deposition by regulating the balance between production and degradation of Abeta in APPV717I transgenic mice
    Jinzhou Tian
    BUCM Neurology Centre, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
    Curr Alzheimer Res 6:118-31. 2009
    ....
  87. ncbi Site-directed mutagenesis of the m2 muscarinic acetylcholine receptor. Analysis of the role of N-glycosylation in receptor expression and function
    C J van Koppen
    Department of Pharmacology, University of Washington, Seattle 98195
    J Biol Chem 265:20887-92. 1990
    ..mutant receptor genes in which the three asparagine codons were substituted by codons for either aspartate (Asp2,3,6), lysine (Lys2,3,6), or glutamine (Gln2,3,6)...
  88. ncbi Beta-amyloid peptide in regulated secretory vesicles of chromaffin cells: evidence for multiple cysteine proteolytic activities in distinct pathways for beta-secretase activity in chromaffin vesicles
    Vivian Y H Hook
    Buck Institute for Age Research, Novato, California 94945, USA
    J Neurochem 81:237-56. 2002
    ..In addition, BACE 1 and BACE 2 were detected in chromaffin vesicles; BACE 1 represented a small fraction of total beta-secretase ..
  89. ncbi [Effect of estrogen-depletion and 17beta-estradiol replacement therapy upon rat hippocampus beta-amyloid generation]
    Hong Qi Yang
    Department of Neurology, Henan Provincial People s Hospital, Zhengzhou 450003, China
    Zhonghua Yi Xue Za Zhi 89:2658-61. 2009
    ..To observe the effects of estrogen depletion and 17beta-estradiol replacement therapy upon ratbeta-amyloid (Abeta) generation and the possible related mechanisms...
  90. ncbi The function of presenilin-1 in amyloid beta-peptide generation and brain development
    P Saftig
    Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, , Germany
    Eur Arch Psychiatry Clin Neurosci 249:271-9. 1999
    ....
  91. ncbi Modeling the tertiary structure of human cathepsin-E
    Kuo Chen Chou
    Gordon Life Science Institute, 13784 Torrey Del Mar, San Diego, CA 92130, USA
    Biochem Biophys Res Commun 331:56-60. 2005
    ..The computed three-dimensional structure of cathepsin-E and the relevant findings might provide useful insights for designing inhibitors with the desired selectivity...
  92. pmc Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers--possibly caused by endoplasmic reticulum stress
    Anna Nogalska
    USC Neuromuscular Center, Department of Neurology, University of Southern California Keck School of Medicine, Good Samaritan Hospital, Los Angeles, CA, USA
    Neurosci Lett 474:140-3. 2010
    ..Accordingly, decreasing BACE1 through a targeted downregulation of its regulatory BACE1-AS, or reducing ER stress, might be therapeutic strategies in s-IBM, assuming that it would not impair any normal cellular functions of BACE1...
  93. ncbi Progress in the development of beta-secretase inhibitors for Alzheimer's disease
    Jeffrey S Albert
    CNS Discovery Research, AstraZeneca Pharmaceuticals, 1800 Concord Pike, P O Box 15437, Wilmington, DE 19850 5437, USA
    Prog Med Chem 48:133-61. 2009
    Since the original identification of BACE in 1999 and until quite recently, BACE was often regarded as a "difficult" drug target, much as renin has proven to be. The reasons for this include the following...
  94. pmc Alternative pathways for production of beta-amyloid peptides of Alzheimer's disease
    Vivian Hook
    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
    Biol Chem 389:993-1006. 2008
    ..One group described the poor kinetics of BACE 1 for cleaving the wild-type (WT) beta-secretase site of APP found in most AD patients...
  95. pmc Potent BACE-1 inhibitor design using pharmacophore modeling, in silico screening and molecular docking studies
    Shalini John
    Department of Biochemistry and Division of Applied Life Science, BK21 Program Environmental Biotechnology National Core Research Center, Gyeongsang National University 900 Gazwa dong, Jinju 660 701, Republic of Korea
    BMC Bioinformatics 12:S28. 2011
    Beta-site amyloid precursor protein cleaving enzyme (BACE-1) is a single-membrane protein belongs to the aspartyl protease class of catabolic enzymes. This enzyme involved in the processing of the amyloid precursor protein (APP)...
  96. pmc Statins inhibit the dimerization of beta-secretase via both isoprenoid- and cholesterol-mediated mechanisms
    Richard B Parsons
    Department of Basic Medical Sciences, St Georges, University of London, Cranmer Terrace, London SW17 0RE, UK
    Biochem J 399:205-14. 2006
    ....
  97. ncbi BACE1 is a newly discovered protein secreted by the pancreas which cleaves enteropeptidase in vitro
    Albrecht Hoffmeister
    Department of Internal Medicine II, University of Leipzig, Leipzig, Germany
    JOP 10:501-6. 2009
    ..Strong BACE1 expression has also been described in pancreatic tissue...
  98. ncbi Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer's disease
    Vivian Hook
    Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093, USA
    Biol Chem 386:931-40. 2005
    ..These findings implicate cathepsin B as beta-secretase in the regulated secretory pathway of brain neurons, suggesting that inhibitors of cathepsin B may be considered as therapeutic agents to reduce A beta in AD...
  99. ncbi Immunotherapy against APP beta-secretase cleavage site improves cognitive function and reduces neuroinflammation in Tg2576 mice without a significant effect on brain abeta levels
    Idan Rakover
    Department of Molecular Microbiology and Biotechnology, George S Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Tel Aviv, Israel
    Neurodegener Dis 4:392-402. 2007
    ..APP processing by beta-secretase, mainly through the endocytic pathway, and overcomes some of the limitations of BACE inhibition...
  100. ncbi In vivo beta-secretase 1 inhibition leads to brain Abeta lowering and increased alpha-secretase processing of amyloid precursor protein without effect on neuregulin-1
    Sethu Sankaranarayanan
    Department of Alzheimer s Research, WP 26A 2000, Merck Research Laboratories, 770, Sumneytown Pike, West Point, PA 19486, USA
    J Pharmacol Exp Ther 324:957-69. 2008
    beta-Secretase (BACE) cleavage of amyloid precursor protein (APP) is one of the first steps in the production of amyloid beta peptide Abeta42, the putative neurotoxic species in Alzheimer's disease...
  101. doi Decreased Neuregulin 1 C-terminal fragment in Brodmann's area 6 of patients with schizophrenia
    Adel Barakat
    Department of Pathology, The University of Melbourne, Parkville, VIC 3010, Australia
    Schizophr Res 124:200-7. 2010
    ..671, p<0.001) but not in the schizophrenic groups. These data suggest that the proteolytic processing of NRG1 is impaired in schizophrenia...

Research Grants64

  1. Multiple Protein Structures in Computational Drug Design
    Heather A Carlson; Fiscal Year: 2013
    ..Inhibitors with new mechanisms are needed to overcome drug resistance in AIDS and pharmacokinetic barriers in treating Alzheimer's disease, respectively. ..
  2. Yong Shen; Fiscal Year: 2014
    ..Thus, elucidating the regulatory mechanisms for BACE1 could identify new potential therapeutic targets and therefore diminish possible side effects that could arise by directly targeting BACE1. ..
  3. MiR-15/107 microRNAs are important genetic regulators in Alzheimer disease
    Peter T Nelson; Fiscal Year: 2012
    ..The overall goal is to produce reagents with optimal "on-target" and minimal "off-target" impact, in order to maximize the potential value of small RNA- based therapeutics. ..
  4. Peter T Nelson; Fiscal Year: 2016
    ..As such the proposed study represents a cutting-edge, data-driven, exploration of a novel disease relevant pathway that may hold promise for our global efforts targeting this major health priority among developing and developed nations. ..
  5. Non-amyloidogenic processing of APP
    Ruben Vidal; Fiscal Year: 2012
    ....
  6. Giuseppina Tesco; Fiscal Year: 2015
    ....
  7. Alzheimers Disease Mechanism & Experimental Therapeutic
    Philip Wong; Fiscal Year: 2009
    ..Furthermore, these studies provide important information regarding potential mechanism based toxicities associated with anti-BACE1 therapy in humans that should be carefully monitored in clinical trials in the future. ..
  8. Casey J Brown; Fiscal Year: 2014
    ..In targeting BACE1-inhibitors with this ribosome display technology, we aim to identify new therapeutics while also establishing technology which can be applied generally in the screening of beta-amino acid containing peptidomimetics. ..
  9. Novel PET imaging agents for early diagnosis of plaque deposition in Alzheimer's
    Padmakar Kulkarni; Fiscal Year: 2010
    ..is significant at a time when a number of therapies for AD are in clinical trial including the use of antioxidants, BACE and gamma secratase inhibitors and metal chelators...
  10. Zhongcong Xie; Fiscal Year: 2016
    ..eukaryotic translation initiatin factor 2[unreadable] (eIF2 [unreadable]-P), [unreadable]-site APP-cleaving enzyme (BACE)1, A[unreadable], microglia activation, and amyloid plaques;and postoperative behavioral changes in mice...
  11. Copper's Role in Brain LRP-mediated Abeta Efflux and Aging
    Rashid Deane; Fiscal Year: 2010
    ..brain A[unreadable] levels by reducing its BBB clearance and 3) no significant changes in protein levels of APP, BACE, IDE, NEP or A[unreadable] putative receptors such as PgP and RAGE in brain microvessels...
  12. Michael J Mullan; Fiscal Year: 2014
    ..NF(B activity after CD40 ligation results in increased generation of A[unreadable], most probably by increasing BACE activity...
  13. Structure and Dynamics of Membrane Proteins from NMR Orientational Constraints
    Homayoun Valafar; Fiscal Year: 2010
    ..These proteins are involved in the Alzheimer's disease (AD) and Parkinson's disease (PD) respectively. ..
  14. Luigi Puglielli; Fiscal Year: 2016
    ..Finally, a combination of biochemical, biophysical, and cellular approaches will be used to assess whether newly identified compounds can serve as additional inhibitory tools (Aim 2B). ..
  15. Paul M Sullam; Fiscal Year: 2016
    ..We will specifically examine the features of GspB and Asp1, Asp2, and Asp3 that contribute to the selective transport of the substrate by the accessory Sec system...
  16. Mechanisms of schizophrenia-like phenotypes in BACE 1 knockout mice
    Alena Savonenko; Fiscal Year: 2010
    ..pool of ErbB4 was significantly reduced as indicated by decreased association of ErbB4 and PSD-95 in the brains of BACE-/- mice...
  17. Riqiang Yan; Fiscal Year: 2016
    ..The knowledge gained from this study will allow us to answer many unmet questions such as whether a significant reduction of BACE1 in the adult would have beneficial effects for reducing or eliminating AD and DS pathologies. ..
  18. Cholinesterase Inhibitors in Alzheimer's Disease
    Debomoy K Lahiri; Fiscal Year: 2012
    ..We will examine i) the effect of novel ChEIs on APP pathway: A? and BACE levels, ii) the effect of substitution of functional groups, iii) APPmRNA 5'-UTR, and iv) synaptic proteins...
  19. Doo Yeon Kim; Fiscal Year: 2016
    ..Moreover, our preliminary data suggest that BACE1 and/or y-secretase inhibitors could affect VGSC function, and be beneficial in normalizing membrane excitability in AD patients with elevated BACE1 activity. ..
  20. Regulation of APP Pathway Gene Promoters in Alzheimer's
    Debomoy K Lahiri; Fiscal Year: 2011
    ..from an increase in APP expression, or in its proteolytic processing by the limiting beta-APP cleaving enzyme (BACE)...
  21. p75NTR-Ceramide Signaling in Alzheimer?s Disease
    Luigi Puglielli; Fiscal Year: 2012
    ..Finally, the long-term goal of this project is consistent with the mission of the Geriatric Research, Education and Clinical Center (GRECC) of this VA Hospital. ..
  22. KIMBERLY SHAUNTAE POINT DU JOUR; Fiscal Year: 2014
    ....
  23. Pre-clinical Development of a Therapeutic for Alzheimer's Disease
    Daniel Paris; Fiscal Year: 2011
    ..Archer) and the Roskamp Institute have jointly developed A2-lowering drugs which indirectly inhibit BACE and reduce amyloid accumulation whilst preserving cognitive function in transgenic models of the disease...
  24. CutA interacts with BACE1 and participates in Alzheimer's disease
    Yunwu Zhang; Fiscal Year: 2012
    ..Together, our results will elucidate the involvement of CutA in AD and the underlying mechanism, identifying a new potential therapeutic target for disease intervention. ..
  25. Aging and Alzheimer's Disease Potential Link with IGF1-R
    Luigi Puglielli; Fiscal Year: 2012
    ..The long-term objective of this proposal is to expand upon our findings and fully characterize the molecular pathway that we have identified. This will allow us to design new pharmacologic approaches for the prevention of AD. ..
  26. Regulatory RNAs as mediators and biomarkers in Alzheimer's Disease
    CLAES ROBERT WAHLESTEDT; Fiscal Year: 2012
    ..Understanding the mechanisms by which BACE1 is regulated may reveal important insights into the pathogenesis of AD, and lead to the development of novel therapeutics and AD biomarkers. ..
  27. Diego E Rincon-Limas; Fiscal Year: 2014
    ..the following specific aims: (1) Characterize the protective activity of secHsp70 in flies expressing human APP and BACE. Our working hypothesis is that secHsp70 will prevent or delay the formation of extracellular proteotoxic ..
  28. NARP AND GLUTAMATE RECEPTOR CLUSTERING
    Paul F Worley; Fiscal Year: 2012
    ..In ongoing studies, we have discovered a molecular complex that includes mGluR, neural pentraxins, TACE and BACE. Like TACE, BACE functions to cleave the extracellular (or luminal) domain of transmembrane proteins, and is the ..
  29. Riqiang Yan; Fiscal Year: 2016
    ..abstract_text> ..
  30. CHRISTOPHER MARK NORRIS; Fiscal Year: 2016
    ..quantify levels of A?40 and A?42 in soluble and insoluble hippocampal tissue fractions, and Westerns used to assess BACE protein expression...
  31. MOHAMED HASSAN FARAH; Fiscal Year: 2016
    ..The proposed studies are highly relevant because faster rate of outgrowth associated with BACE1 inhibition could be useful in speeding nerve regeneration in human conditions. ..
  32. Chu Chen; Fiscal Year: 2016
    ....
  33. Mark W Albers; Fiscal Year: 2014
    ..abstract_text> ..
  34. Gene Interactions in a Model of Alzheimer's Disease
    Frank M LaFerla; Fiscal Year: 2012
    ..Stress is a risk factor for AD We recently reported that stress-level glucocorticoids increase APP, BACE, and A[unreadable] levels as well as augmenting tau...
  35. Masuo Ohno; Fiscal Year: 2014
    ....
  36. Identification of an Abeta fragment produced by BACE2
    Donald C Lo; Fiscal Year: 2012
    ....
  37. Paul M Sullam; Fiscal Year: 2016
    ..the interactions of the accessory Sec system that mediate GspB export, and in particular, the roles of Asp1, Asp2, and Asp3...
  38. Role of BACE in the pathogenesis of Alzheimer's disease after head trauma
    Giuseppina Tesco; Fiscal Year: 2013
    ..Beta-site APP-cleaving enzyme (BACE) has been identified as beta-secretase...
  39. MICHAEL ANDRE GITCHO; Fiscal Year: 2016
    ..For those suffering from Alzheimer's disease there is an age-dependent increase BACE activity increasing APP processing leading to accelerated neurodegeneration...
  40. APP/AB/Tau biochemistry in transgenic mice, familial and sporadic AD
    Alex E Roher; Fiscal Year: 2013
    ..precursor protein (APP), presenilin (PS), the microtubule protein tau, [unreadable]-amyloid cleaving enzyme-1 (BACE-1), and a-synuclein have provided tools to investigate both the pathogenesis and the efficacy of treatments for ..
  41. Zvonimir S Katusic; Fiscal Year: 2016
    ..We expect the results of our proposed studies will establish cerebrovascular endothelium as a critical target in the prevention of AD thereby directing and concentrating therapeutic focus on the cerebral circulation. ..
  42. Edwards A Park; Fiscal Year: 2014
    ..Successful completion of this project will be instrumental for future pursuing potential combination therapy between agents promoting retinoid signaling and insulin- sensitization (PPARgamma agonists etc). ..
  43. Gopal Thinakaran; Fiscal Year: 2015
    ..Our studies will uncover novel and significant insights on differential regulation of AP secretase localization and function by S-palmitoylation in cultured hippocampal neurons and in vivo. ..
  44. Jun Tan; Fiscal Year: 2016
    ..At the end of these experiments, these studies will provide the molecular basis for the future development of OG as novel and pharmacologically safe agents for Alzheimer's disease prevention/treatment. ..
  45. Brian Giunta; Fiscal Year: 2015
    ..It should lay the foundation for effective strategies to prevent these interactions between Tat and HAART in the future in the context of a known HAART-mediated pathophysiological mechanism. ..
  46. Study on Thalidomide as BACE1 inhibitor in Alzhiemer's disease
    Marwan N Sabbagh; Fiscal Year: 2010
    ..We propose that Thalidomide may represent a BACE1 inhibitor. ..
  47. ROBERT J VASSAR; Fiscal Year: 2016
    ..Together, these Aims will determine the overall utility of BACE1 inhibition as an AD therapeutic strategy in terms of its potential side effect profile and efficacy. ..
  48. Characterization of ATXN1 in APP processing and AD pathogenesis
    CAN MARTIN ZHANG; Fiscal Year: 2012
    ..abstract_text> ..
  49. Plasma AB as a Surrogate Genetic Marker for LOAD
    Steven G Younkin; Fiscal Year: 2012
    ....
  50. Riqiang Yan; Fiscal Year: 2016
    ....
  51. Beta Secretase Inhibition for Treating Alzheimer's Disease
    JORDAN J TANG; Fiscal Year: 2011
    DESCRIPTION (provided by applicant): Memapsin 2 (beta-secretase, BACE) is the protease that initiated the cleavage of beta-amyloid precursor protein (APR) leading to the production of amyloid-beta (Abeta)...
  52. Nectin-1: Synaptic processing and functions
    Howard J Federoff; Fiscal Year: 2010
    ..Subsequently, we examine whether expression of trans-dominant nectin-1 mutants will affect hippocampal dependent learning ..
  53. Cell Biology of Presenilin 1 and Associated Proteins
    Gopal Thinakaran; Fiscal Year: 2012
    ..abstract_text> ..
  54. Effect of Beta-secretase Inhibitors on Pancreatic Cancer Cells
    Joyce C Solheim; Fiscal Year: 2013
    ..Furthermore, in addition to their translational potential, these studies are expected to provide new perspectives on the basic molecular regulation of pancreatic cancer cell survival. ..
  55. Giulio Maria Pasinetti; Fiscal Year: 2015
    ..This will allow us to eventually identify novel approaches to prevent or attenuate AD phenotypes through PGC-1a-mediated responses that could be translated into AD therapies. ..
  56. BACE1-NEUREGULIN-ErbB4 SIGNALING IN OLFACTORY MODELS OF PSYCHOSIS
    Vassilis E Koliatsos; Fiscal Year: 2010
    ....
  57. Randall J Bateman; Fiscal Year: 2016
    ..Subjects will receive either drug of placebo for two years to determine engagement of the CNS mechanism of action and downstream AD biomarkers. ..
  58. Inhibitors of beta-Amyloid Production in Alzheimer's
    Gregory Hook; Fiscal Year: 2007
    ..Specifically, we will assess the affects of these peptidomimetics on beta-amyloid secretion in primary neuronal cultures and in vivo. ..
  59. Role of Anesthetic Isoflurane in Alzheimer's Disease: In Vivo Investigation
    Zhongcong Xie; Fiscal Year: 2009
    ..activation, apoptosis, levels of full-length-APP, APP-C-terminal fragments and Ab, and levels and activities of BACE and 3-secretase will be determined...
  60. ESTROGEN MODULATION OF BRAIN ABETA METABOLISM IN VIVO
    Samuel Gandy; Fiscal Year: 2004
    ..estrogen action on brain AB could involve the inhibition of B-secretase activity, we will measure soluble APP-D and BACE mRNA levels in the brains of control, ovx and pharmacologically treated guinea pigs...
  61. Philip Williams; Fiscal Year: 2014
    ....
  62. Novel Mechanisms of RanBP9 in APP Pathogenesis
    David E Kang; Fiscal Year: 2012
    ....
  63. Neuronal endolysosome involvement in HIV-1 Tat-induced amyloid beta accumulation
    JONATHAN DAVID GEIGER; Fiscal Year: 2013
    ..2) Determine mechanisms whereby Tat elevates endolysosome pH, thus enhancing BACE-1 activity in favor of A? production...
  64. Development of RNAi as Treatment for Neurodegeneration
    KENNETH KOSIK; Fiscal Year: 2005
    ..The scientific goals of our program are to develop RNAi approaches to 'knock-down' expression of BACE, an enzyme involved in the cleavage of APP to A-beta...