Michael Wolfe

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. ncbi request reprint Presenilin: running with scissors in the membrane
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cell 131:215-21. 2007
  2. pmc Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing
    Eleanor Peacey
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, 77 Avenue Louis Pasteur, HIM 754, Boston, MA 02115, USA
    Nucleic Acids Res 40:9836-49. 2012
  3. pmc Toward the structure of presenilin/γ-secretase and presenilin homologs
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H I M 754, Boston, MA 02115 USA Electronic address
    Biochim Biophys Acta 1828:2886-97. 2013
  4. ncbi request reprint Processive proteolysis by γ-secretase and the mechanism of Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H I M 754, Boston, MA 02115, USA
    Biol Chem 393:899-905. 2012
  5. pmc γ-Secretase inhibitors and modulators for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    J Neurochem 120:89-98. 2012
  6. pmc Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer
    Jian Ping Lu
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Mol Cancer 9:304. 2010
  7. ncbi request reprint Intramembrane proteolysis: theme and variations
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Science 305:1119-23. 2004
  8. ncbi request reprint Gamma-secretase: structure, function, and modulation for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Curr Top Med Chem 8:2-8. 2008
  9. ncbi request reprint The gamma-secretase complex: membrane-embedded proteolytic ensemble
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Biochemistry 45:7931-9. 2006
  10. pmc When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, Harvard Institute of Medicine 754, Boston, Massachusetts 02115, USA
    EMBO Rep 8:136-40. 2007

Research Grants

Collaborators

Detail Information

Publications82

  1. ncbi request reprint Presenilin: running with scissors in the membrane
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cell 131:215-21. 2007
    ..Here we highlight recent progress in deciphering the role of presenilin/gamma-secretase in biology and medicine and pose key questions for future study...
  2. pmc Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing
    Eleanor Peacey
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, 77 Avenue Louis Pasteur, HIM 754, Boston, MA 02115, USA
    Nucleic Acids Res 40:9836-49. 2012
    ..This general bipartite antisense strategy could be employed to modulate other splicing events that are regulated by RNA secondary structure...
  3. pmc Toward the structure of presenilin/γ-secretase and presenilin homologs
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H I M 754, Boston, MA 02115 USA Electronic address
    Biochim Biophys Acta 1828:2886-97. 2013
    ..This article is part of a Special Issue entitled: Intramembrane Proteases...
  4. ncbi request reprint Processive proteolysis by γ-secretase and the mechanism of Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H I M 754, Boston, MA 02115, USA
    Biol Chem 393:899-905. 2012
    ..That is, the reduction of this particular proteolytic function of presenilin, not its endoproteolytic activity, may lead to the neurotoxic gain of function...
  5. pmc γ-Secretase inhibitors and modulators for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    J Neurochem 120:89-98. 2012
    ..The various chemical types of inhibitors and modulators will be discussed, along with their use as probes for basic biology and their potential as AD therapeutics...
  6. pmc Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates δ-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer
    Jian Ping Lu
    Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
    Mol Cancer 9:304. 2010
    ....
  7. ncbi request reprint Intramembrane proteolysis: theme and variations
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Science 305:1119-23. 2004
    ....
  8. ncbi request reprint Gamma-secretase: structure, function, and modulation for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Curr Top Med Chem 8:2-8. 2008
    ..A better structural and mechanistic understanding of gamma-secretase should ultimately allow structure-based design of more potent and selective modulators...
  9. ncbi request reprint The gamma-secretase complex: membrane-embedded proteolytic ensemble
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Biochemistry 45:7931-9. 2006
    ..Elucidation of detailed structural features of gamma-secretase and other membrane-embedded proteases is the next frontier in understanding how these enzymes carry out hydrolysis within the lipid bilayer...
  10. pmc When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, Harvard Institute of Medicine 754, Boston, Massachusetts 02115, USA
    EMBO Rep 8:136-40. 2007
    ..In this review, a unifying hypothesis is presented that puts forward a biochemical mechanism by which slower less-efficient forms of the protease can result in a greater proportion of 42-residue Abeta...
  11. ncbi request reprint APP at a glance
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA, USA
    J Cell Sci 120:3157-61. 2007
  12. ncbi request reprint gamma-Secretase modulators
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Curr Alzheimer Res 4:571-3. 2007
    ..Structural modification of these gamma-secretase modulators through medicinal chemistry should lead to in vivo active agents suitable for clinical trials...
  13. pmc Gamma-secretase inhibition and modulation for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Curr Alzheimer Res 5:158-64. 2008
    ..The identification of other modulators in a variety of structural classes raise the hope that more promising agents will soon be in the pipeline...
  14. pmc Inhibition and modulation of gamma-secretase for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Neurotherapeutics 5:391-8. 2008
    ..Such modulators have been discovered and advanced, with one compound in late-phase clinical trials, renewing interest in gamma-secretase as a therapeutic target...
  15. ncbi request reprint Tau mutations in neurodegenerative diseases
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 284:6021-5. 2009
    ....
  16. pmc Selective amyloid-beta lowering agents
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    BMC Neurosci 9:S4. 2008
    ..The mechanism by which these agents lower Abeta is unknown, but these compounds may ultimately reveal new targets for AD therapeutics...
  17. doi request reprint gamma-Secretase in biology and medicine
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115 USA
    Semin Cell Dev Biol 20:219-24. 2009
    ..Inhibition of Notch signaling by gamma-secretase inhibitors, which is undesirable for the prevention or treatment of Alzheimer's disease, may be beneficial for the treatment of a variety of cancers...
  18. pmc Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Biol Chem 391:839-47. 2010
    ..However, the SPPs work as single polypeptides without the need for cofactors and otherwise appear to be simple model systems for presenilin in the gamma-secretase complex. SPP biology, structure, and inhibition will also be discussed...
  19. ncbi request reprint Alzheimer's Disease Drug Discovery--11th International Conference--Promising New Therapeutic Approaches. 27-28 September 2010, Jersey City, NJ, USA
    Michael S Wolfe
    Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    IDrugs 13:825-7. 2010
    ....
  20. ncbi request reprint Alzheimer's Disease Drug Discovery--11th International Conference--Targeting Pathological Tau. 27-28 September 2010, Jersey City, NJ, USA
    Michael S Wolfe
    Brigham and Women s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
    IDrugs 13:828-9. 2010
    ....
  21. ncbi request reprint Gamma-secretase--intramembrane protease with a complex
    Michael S Wolfe
    Center for Neurologic Diseases at Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Sci Aging Knowledge Environ 2003:PE7. 2003
    ..Understanding the mechanism of this unusual enzyme is important, as it is both a key therapeutic target and a founding member of a newly discovered class of intramembrane-cleaving proteases...
  22. ncbi request reprint Secretase as a target for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, H I M 626, Boston, MA 02115, USA
    Curr Top Med Chem 2:371-83. 2002
    ..The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns...
  23. ncbi request reprint gamma-Secretase inhibitors as molecular probes of presenilin function
    M S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Mol Neurosci 17:199-204. 2001
    ..Heterodimeric presenilin appears to be the catalytic portion of a multi-protein gamma-secretase complex...
  24. ncbi request reprint Continuing strategies for inhibiting Alzheimer's gamma-secretase
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Mol Neurosci 19:83-7. 2002
    ..These peptides inhibited gamma-secretase in the low micromolar range in cell culture, suggesting that they indeed mimick the APP substrate conformation...
  25. ncbi request reprint APP, Notch, and presenilin: molecular pieces in the puzzle of Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, H I M 626, Boston, MA 02115, USA
    Int Immunopharmacol 2:1919-29. 2002
    ..In light of these findings, the potential of gamma-secretase vis-à-vis beta-secretase as therapeutic targets for the prevention or treatment of AD will be discussed...
  26. ncbi request reprint Biochemistry. Intramembrane proteases--mixing oil and water
    Michael S Wolfe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Science 296:2156-7. 2002
  27. ncbi request reprint Therapeutic strategies for Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, HIM 754, Boston, Massachusetts 02115, USA
    Nat Rev Drug Discov 1:859-66. 2002
    ..The progress of these and other approaches raises the hope that effective agents for the prevention and treatment of Alzheimer's disease will be available in the near future...
  28. ncbi request reprint Purification and characterization of the human gamma-secretase complex
    Patrick C Fraering
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Biochemistry 43:9774-89. 2004
    ....
  29. ncbi request reprint Notch and the amyloid precursor protein are cleaved by similar gamma-secretase(s)
    W Taylor Kimberly
    Center for Neurologic Diseases, Brigham and Women s Hospital, and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
    Biochemistry 42:137-44. 2003
    ..These data resolve some of the apparent conflicts and strongly indicate that Notch and APP are proteolyzed by the same enzyme(s)...
  30. ncbi request reprint Presenilin endoproteolysis mediated by an aspartyl protease activity pharmacologically distinct from gamma-secretase
    William A Campbell
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurochem 85:1563-74. 2003
    ..Therefore, presenilinase has characteristics of an aspartyl protease, but this activity is distinct from gamma-secretase...
  31. ncbi request reprint Detergent-dependent dissociation of active gamma-secretase reveals an interaction between Pen-2 and PS1-NTF and offers a model for subunit organization within the complex
    Patrick C Fraering
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Biochemistry 43:323-33. 2004
    ..Taken together, our results demonstrate that Pen-2 interacts with PS-NTF within active gamma-secretase and offer a model for how the components of active gamma-secretase interact physically with each other...
  32. pmc Deducing the transmembrane domain organization of presenilin-1 in gamma-secretase by cysteine disulfide cross-linking
    Anna Y Kornilova
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
    Biochemistry 45:7598-604. 2006
    ..These findings suggest that the conserved cysteines of TMD1 and TMD8 contribute to or allosterically interact with the active site of gamma-secretase...
  33. ncbi request reprint Shutting down Alzheimer's
    Michael S Wolfe
    Brigham and Women s Hospital, Harvard Medical School, USA
    Sci Am 294:72-9. 2006
  34. ncbi request reprint Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging
    Oksana Berezovska
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 23:4560-6. 2003
    ..We interpret these results to suggest that there is a noncatalytic docking site closely associated with PS1-gamma-secretase...
  35. ncbi request reprint Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo
    Dominic M Walsh
    Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Nature 416:535-9. 2002
    ....
  36. pmc The initial substrate-binding site of gamma-secretase is located on presenilin near the active site
    Anna Y Kornilova
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 102:3230-5. 2005
    ....
  37. ncbi request reprint Proteolysis of chimeric beta-amyloid precursor proteins containing the Notch transmembrane domain yields amyloid beta-like peptides
    Jimin Zhang
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Biol Chem 277:15069-75. 2002
    ..We conclude that gamma-secretase can cleave near the middle of the Notch TMD, that Abeta-like peptides may arise during Notch processing, and that the pre-TMD sequence of the substrate influences recognition or binding by the enzyme...
  38. pmc Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate
    William P Esler
    Center for Neurologic Diseases, Brigham and Women s Hospital and Program in Neuroscience, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 99:2720-5. 2002
    ....
  39. ncbi request reprint The secretases of Alzheimer's disease
    Michael S Wolfe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Curr Top Dev Biol 54:233-61. 2003
  40. pmc gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site
    Patrick C Fraering
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 280:41987-96. 2005
    ..Drugs targeting the gamma-secretase nucleotide-binding site represent an attractive strategy for safely treating Alzheimer disease...
  41. pmc Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2
    W Taylor Kimberly
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 100:6382-7. 2003
    ..These findings suggest that the four membrane proteins comprise the limiting components of gamma-secretase and coassemble to form the active enzyme in mammalian cells...
  42. ncbi request reprint Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates
    Stephanie Baulac
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Neurobiol Dis 14:194-204. 2003
    ..Immunofluorescent staining of the individual gamma-secretase components supported our biochemical evidence that the gamma-secretase components assemble into the proteolytically active gamma-secretase complex in the Golgi/TGN compartment...
  43. ncbi request reprint Probing pockets S2-S4' of the gamma-secretase active site with (hydroxyethyl)urea peptidomimetics
    William P Esler
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Womens Hospital, Boston, MA 02115, USA
    Bioorg Med Chem Lett 14:1935-8. 2004
    ..A compound spanning P2-P3' was identified as a low nM inhibitor of gamma-secretase activity both in cells and under cell-free conditions...
  44. pmc Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity
    Sinisa Urban
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 102:1883-8. 2005
    ..This analysis promises to help reveal the biochemical mechanisms and biological roles of this most widely conserved membrane protein family...
  45. ncbi request reprint A C-terminal region of signal peptide peptidase defines a functional domain for intramembrane aspartic protease catalysis
    Saravanakumar Narayanan
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    J Biol Chem 282:20172-9. 2007
    ..The discovery of minimal requirements for intramembrane proteolysis should facilitate mechanistic and structural analysis and help define general biochemical principles of hydrolysis in a hydrophobic environment...
  46. ncbi request reprint Differential effects of inhibitors on the gamma-secretase complex. Mechanistic implications
    Anna Y Kornilova
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 278:16470-3. 2003
    ....
  47. ncbi request reprint Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin
    Matthew J LaVoie
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Biol Chem 278:37213-22. 2003
    ....
  48. ncbi request reprint Intramembrane proteolysis by presenilin and presenilin-like proteases
    Weiming Xia
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    J Cell Sci 116:2839-44. 2003
    ..SPP cuts type II membrane proteins, illustrating that PS-like proteases play a key role in intramembrane proteolysis of single-pass membrane proteins oriented in either direction...
  49. ncbi request reprint Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila
    Craig A Micchelli
    Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts, USA
    FASEB J 17:79-81. 2003
    ....
  50. ncbi request reprint Identity and function of gamma-secretase
    W Taylor Kimberly
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Neurosci Res 74:353-60. 2003
    ..Recent findings suggest that these four proteins are sufficient to reconstitute the active gamma-secretase complex and that together they mediate the cell surface signaling of a variety of receptors via intramembrane proteolysis...
  51. ncbi request reprint Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation
    W Taylor Kimberly
    Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 277:35113-7. 2002
    ....
  52. pmc Distinct pharmacological effects of inhibitors of signal peptide peptidase and gamma-secretase
    Toru Sato
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 283:33287-95. 2008
    ....
  53. ncbi request reprint Stereochemical analysis of (hydroxyethyl)urea peptidomimetic inhibitors of gamma-secretase
    Pancham Bakshi
    Center for Neurologic Disease, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Med Chem 47:6485-9. 2004
    ..Although typically less potent than their L-peptidomimetic counterparts, selected all D-amino acid containing analogues were equipotent to their counterparts in a cell-based assay when incubated for extended times...
  54. ncbi request reprint A high-throughput screen to identify inhibitors of amyloid beta-protein precursor processing
    Pancham Bakshi
    Center for Neurologic Diseases and Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Biomol Screen 10:1-12. 2005
    ..In principle, this sensitive, specific, and quantitative assay may be useful for identifying both inhibitors and stimulators of APP processing...
  55. pmc Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling
    Andrew P Weng
    Departments of Pathology, Brigham and Women s Hospital, Harvard Medical School Department of Adult Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA
    Mol Cell Biol 23:655-64. 2003
    ....
  56. doi request reprint Promotion of BACE1 mRNA alternative splicing reduces amyloid beta-peptide production
    Karen R Mowrer
    Center for Neurologic Diseases, Brigham Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 283:18694-701. 2008
    ....
  57. ncbi request reprint Designed helical peptides inhibit an intramembrane protease
    Chittaranjan Das
    Center for Neurologic Diseases, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Am Chem Soc 125:11794-5. 2003
    ..These findings are consistent with helical peptides interacting with the initial substrate docking site of gamma-secretase, suggesting a general strategy for the development of potent and specific inhibitors of intramembrane proteases...
  58. pmc From rhomboid function to structure and back again
    Raquel L Lieberman
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 104:8199-200. 2007
  59. ncbi request reprint Active gamma-secretase complexes contain only one of each component
    Toru Sato
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    J Biol Chem 282:33985-93. 2007
    ..Taken together, these results demonstrate that the stoichiometry of gamma-components presenilin:Pen-2:nicastrin:Aph-1 is 1:1:1:1...
  60. doi request reprint 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...
  61. pmc Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution
    Pamela Osenkowski
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    J Mol Biol 385:642-52. 2009
    ..The structure reveals several domains on the extracellular side, three solvent-accessible low-density cavities, and a potential substrate-binding surface groove in the transmembrane region of the complex...
  62. ncbi request reprint Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinflammatory drugs
    Toru Sato
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Biochemistry 45:8649-56. 2006
    ..Together, these findings suggest that SPP and presenilin share certain biochemical properties, including a conserved drug-binding site for allosteric modulation of substrate proteolysis...
  63. pmc Membrane-embedded protease poses for photoshoot
    Raquel L Lieberman
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 104:401-2. 2007
  64. ncbi request reprint Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase
    Frédéric Bihel
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
    J Med Chem 47:3931-3. 2004
    ..Here, we used solid-phase synthesis to generate a new series of helical peptides as gamma-secretase inhibitors, one of which, 11, showed an IC(50) of 140 pM in a cell-free enzyme assay...
  65. pmc Mitoxantrone analogues as ligands for a stem-loop structure of tau pre-mRNA
    Yang Liu
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, H I M 754, Boston, Massachusetts 02115, USA
    J Med Chem 52:6523-6. 2009
    ..These findings establish essential structure-activity relationships to further optimize the activity of this promising class of compounds...
  66. ncbi request reprint Identification of tau stem loop RNA stabilizers
    Christine P Donahue
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biomol Screen 12:789-99. 2007
    ..These assays should be applicable to the general problem of identifying small molecules that interact with mRNA secondary structures...
  67. pmc Stabilization of the tau exon 10 stem loop alters pre-mRNA splicing
    Christine P Donahue
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 281:23302-6. 2006
    ..Together these results validate the stem loop as a bona fide structure regulating tau exon 10 splicing...
  68. ncbi request reprint Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis
    Yoshiharu Miyamoto
    Departments of Surgery, Oncology, and Pathology, The Sidney Kimmel Cancer Center at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
    Cancer Cell 3:565-76. 2003
    ..These findings suggest that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells...
  69. ncbi request reprint Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage
    Jon W Cowan
    Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0012, USA
    J Biol Chem 280:19331-42. 2005
    ..These data indicate that the GHR is subject to sequential proteolysis by metalloprotease and gamma-secretase activities and may suggest GH-independent roles for the GHR...
  70. pmc A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP
    Malcolm A Leissring
    Laboratory of Molecular Neuropathogenesis, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA
    Proc Natl Acad Sci U S A 99:4697-702. 2002
    ....
  71. pmc A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis
    Eric H Schroeter
    Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 100:13075-80. 2003
    ..We propose that gamma-secretase contains a PS dimer in its catalytic core, that binding of substrate is at a site separate from the active site, and that substrate is cleaved at the interface of two PS molecules...
  72. ncbi request reprint Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor
    Andrew C Nyborg
    Department of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA
    J Biol Chem 279:15153-60. 2004
    ..Collectively these data suggest that SPP exists in vivo as a functional dimer...
  73. ncbi request reprint Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway
    Yung Feng Liao
    Laboratory of Molecular Neurobiology, Institute of Zoology, Academia Sinica, Taipei 115, Taiwan
    J Biol Chem 279:49523-32. 2004
    ..Our studies provide direct evidence that cytokine-elicited signaling cascades control Abeta production by modulating gamma-secretase activity...
  74. ncbi request reprint The search for gamma-secretase and development of inhibitors
    Jui Yi Tsai
    PPG Industrial, 440 College Park Drive, Monroeville, PA 15146, USA
    Curr Med Chem 9:1087-106. 2002
    ..In this article, we review the current knowledge of gamma-secretase biochemistry and cell biology and the development of inhibitors of this important therapeutic target...
  75. pmc Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores
    Vlado K Lazarov
    Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA
    Proc Natl Acad Sci U S A 103:6889-94. 2006
    ..Our reconstructed 3D map provides a physical basis for hydrolysis of transmembrane substrates within a lipid bilayer and release of the products into distinct subcellular compartments...
  76. ncbi request reprint The surface of articular cartilage contains a progenitor cell population
    Gary P Dowthwaite
    Cardiff School of Biosciences and Cardiff Institute of Tissue Engineering and Repair, Cardiff University, PO Box 911, Museum Avenue, Cardiff CF10 3US, UK
    J Cell Sci 117:889-97. 2004
    ....
  77. ncbi request reprint Inhibition of Notch signaling biases rat thymocyte development towards the NK cell lineage
    Jens van den Brandt
    Institute of Virology and Immunobiology, University of Wuerzburg, Wuerzburg, Germany
    Eur J Immunol 34:1405-13. 2004
    ..Collectively, this identifies the lineage decision of NK/T precursor cells as an important site of Notch action in rat thymocytes...
  78. pmc Substrate-targeting gamma-secretase modulators
    Thomas L Kukar
    Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
    Nature 453:925-9. 2008
    ..These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets...
  79. ncbi request reprint Substituted thiazolamide coupled to a redox delivery system: a new gamma-secretase inhibitor with enhanced pharmacokinetic profile
    Younes Laras
    INSERM U 623, Institut de Biologie du Developpement de Marseille, CNRS Inserm Université de la Méditerranée, Laboratoire de Chimie Biomoleculaire, 13288 Marseille Cedex 09, France
    Org Biomol Chem 3:612-8. 2005
    ..From the obtained results, it is expected that drug will be mainly delivered to the CNS with low diffusion in the peripheral tissues. Consequently the side effects of this gamma-secretase inhibitor on the immune cells could be reduced...
  80. ncbi request reprint Amyloid-lowering isocoumarins are not direct inhibitors of gamma-secretase
    William P Esler
    Nat Cell Biol 4:E110-1; author reply E111-2. 2002
  81. ncbi request reprint Notch signaling augments T cell responsiveness by enhancing CD25 expression
    Scott H Adler
    Departments of Medicine, Institute for Medicine and Engineering, The Abramson Family Cancer Research Institute, University of Pennsylvania Medical Center, Philadelphia, PA 19104, USA
    J Immunol 171:2896-903. 2003
    ..These data suggest an important role for Notch signaling during CD4(+) T cell responses, which operates through augmenting a positive feedback loop involving IL-2 and its high affinity receptor...

Research Grants23

  1. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael S Wolfe; Fiscal Year: 2010
    ..Small organic molecules will be used as probes to characterize this enzyme, elucidate how it works, and explore its potential as a therapeutic target. ..
  2. The Role of Presenilin in Gamma-Secretase Activity
    Michael Wolfe; Fiscal Year: 2009
    ..for substrate-protease recognition? (3) What is the role of Aph-1 and NCT in the assembly and activity of the protease complex? (4) How do mutations in PS that cause familial AD alter the specificity and activity of gamma-secretase? ..
  3. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2003
    ..Finally, nonpeptide analogues of these transition-state mimics will be developed using combinatorial chemistry as part of a strategy to identify metabolically stable compounds that block y-secretase activity in whole organisms. ..
  4. The Role of Presenilin in Gamma-Secretase Activity
    Michael Wolfe; Fiscal Year: 2007
    ..for substrate-protease recognition? (3) What is the role of Aph-1 and NCT in the assembly and activity of the protease complex? (4) How do mutations in PS that cause familial AD alter the specificity and activity of gamma-secretase? ..
  5. The Role of Presenilin in Gamma-Secretase Activity
    Michael Wolfe; Fiscal Year: 2007
    ..recognition? (3) What is the role of Aph-1 and NCT in the assembly and activity of the protease complex? (4) How do mutations in PS that cause familial AD alter the specificity and activity of y-secretase? ..
  6. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2001
    ..Finally, nonpeptide analogues of these transition-state mimics will be developed using combinatorial chemistry as part of a strategy to identify metabolically stable compounds that block y-secretase activity in whole organisms. ..
  7. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2007
    ..Small organic molecules will be used as probes to characterize this enzyme, elucidate how it works, and explore its potential as a therapeutic target. ..
  8. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2009
    ..Small organic molecules will be used as probes to characterize this enzyme, elucidate how it works, and explore its potential as a therapeutic target. ..
  9. Structure and mechanism of signal peptide peptidase
    Michael Wolfe; Fiscal Year: 2007
    ..A structure of SPP would provide tremendous insight into the workings of an unusual new class of enzymes that are critical to both biology and medicine. ..
  10. The Role of Presenilin in Gamma-Secretase Activity
    Michael Wolfe; Fiscal Year: 2006
    ..for substrate-protease recognition? (3) What is the role of Aph-1 and NCT in the assembly and activity of the protease complex? (4) How do mutations in PS that cause familial AD alter the specificity and activity of gamma-secretase? ..
  11. ROLE OF PRESENILIN IN GAMMA-SECRETASE ACTIVITY
    Michael Wolfe; Fiscal Year: 2002
    ..enzyme? Does PS1 mediate this proteolysis? (3) Are separate gamma-secretases responsible for A-beta40 and A-beta42 formation? How do FAD-mutant APP and presenilins alter gamma-secretase processing to increase A-beta42 production? ..
  12. ROLE OF PRESENILIN IN GAMMA-SECRETASE ACTIVITY
    Michael Wolfe; Fiscal Year: 2003
    ..enzyme? Does PS1 mediate this proteolysis? (3) Are separate gamma-secretases responsible for A-beta40 and A-beta42 formation? How do FAD-mutant APP and presenilins alter gamma-secretase processing to increase A-beta42 production? ..
  13. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2004
    ..Finally, nonpeptide analogues of these transition-state mimics will be developed using combinatorial chemistry as part of a strategy to identify metabolically stable compounds that block y-secretase activity in whole organisms. ..
  14. ROLE OF PRESENILIN IN GAMMA-SECRETASE ACTIVITY
    Michael Wolfe; Fiscal Year: 2004
    ..enzyme? Does PS1 mediate this proteolysis? (3) Are separate gamma-secretases responsible for A-beta40 and A-beta42 formation? How do FAD-mutant APP and presenilins alter gamma-secretase processing to increase A-beta42 production? ..
  15. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2005
    ..Finally, nonpeptide analogues of these transition-state mimics will be developed using combinatorial chemistry as part of a strategy to identify metabolically stable compounds that block y-secretase activity in whole organisms. ..
  16. Molecular Probes for Alzheimer's Gamma-Secretase
    Michael Wolfe; Fiscal Year: 2002
    ..Finally, nonpeptide analogues of these transition-state mimics will be developed using combinatorial chemistry as part of a strategy to identify metabolically stable compounds that block y-secretase activity in whole organisms. ..
  17. Structure and mechanism of signal peptide peptidase
    Michael Wolfe; Fiscal Year: 2009
    ..A structure of SPP would provide tremendous insight into the workings of an unusual new class of enzymes that are critical to both biology and medicine. ..
  18. The Role of Presenilin in Gamma-Secretase Activity
    Michael Wolfe; Fiscal Year: 2005
    ..for substrate-protease recognition? (3) What is the role of Aph-1 and NCT in the assembly and activity of the protease complex? (4) How do mutations in PS that cause familial AD alter the specificity and activity of gamma-secretase? ..
  19. ROLE OF PRESENILIN IN GAMMA-SECRETASE ACTIVITY
    Michael Wolfe; Fiscal Year: 2001
    ..enzyme? Does PS1 mediate this proteolysis? (3) Are separate gamma-secretases responsible for A-beta40 and A-beta42 formation? How do FAD-mutant APP and presenilins alter gamma-secretase processing to increase A-beta42 production? ..
  20. Structure and mechanism of signal peptide peptidase
    Michael S Wolfe; Fiscal Year: 2010
    ..A structure of SPP would provide tremendous insight into the workings of an unusual new class of enzymes that are critical to both biology and medicine. ..