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Keywords
Last Name
Institution

Michael S. Wolfe, PH.D.

TitleProfessor of Neurology
InstitutionBrigham and Women's Hospital
DepartmentNeurology
AddressBrigham & Women's Hospital
Ctr for Neurologic Disease
77 Avenue Louis Pasteur
Boston MA 02115
Phone617/525-5511
Fax617/525-5252

 Overview 
 overview
The Wolfe lab studies intramembrane proteases that play critical roles both in normal biology and in human disease. The last place in the cell to expect hydrolysis is within the hydrophobic environment of the lipid bilayer. Nevertheless, a number of multi-pass membrane proteins appear to carry out this seemingly paradoxical process (Wolfe and Kopan, Science, 2004; see publications list for references in this section). Such proteases cut within the transmembrane region of their respective substrates, and consistent with this observation, these proteases contain putative catalytic residues located within transmembrane domains.

The specific focus of the lab has been on the chemistry and biology of gamma-secretase. This protease is critical to the pathogenesis of Alzheimer's disease (Esler and Wolfe, Science, 2001) and to cell differentiation during embryonic development. Small organic inhibitors were developed and used as tools to characterize and identify gamma-secretase (Wolfe et al., J Med Chem, 1998; Wolfe et al., Biochemistry, 1999a). Findings from the lab implicate a multi-pass membrane protein called presenilin as the catalytic component of a larger gamma-secretase complex (Wolfe et al., Nature, 1999; Esler et al., Nat Cell Biol, 2000). Missense mutations in presenilin cause hereditary Alzheimer's disease, and these mutations specifically affect gamma-secretase activity.

The lab found that presenilin and a presenilin-associated protein called nicastrin copurify with gamma-secretase activity from an immobilized inhibitor, evidence that nicastrin is also a member of the protease complex (Esler et al., Proc Natl Acad Sci USA, 2002). Moreover, a gamma-secretase substrate also copurified, suggesting an initial substrate docking site on the protease complex distinct from the active site. Helical peptides designed to interact with this docking site can potently inhibit gamma-secretase activity both in cell-free and cell-based assays (Das et al., J Am Chem Soc, 2003; Kornilova et al., Proc Natl Acad Sci USA, 2005). Most recently, the lab determined the stoichiometry of the active gamma-secretase complex, which had been unknown (and, with respect to presenilin, controversial). The four essential components (presenilin, nicastrin, Aph-1 and Pen-2) are each represented only once per complex (Sato et al., J Biol Chem, 2007).

The lab has also discovered a nucleotide binding site on the gamma-secretase complex. Small organic molecules that interact with this site can selectively block gamma-secretase proteolysis of the amyloid beta-protein precursor (APP), critical to the pathogenesis of Alzheimer’s disease, without affecting proteolysis of an alternative substrate, the Notch receptor. Notch signaling, critical in many cell differentiation events, requires proteolysis by gamma-secretase (De Strooper et al., Nature, 1999), and blocking Notch signaling with gamma-secretase inhibitors causes severe toxicity in mice. The finding that compounds can selectively block the cleavage of APP without affecting that of Notch (Fraering et al., J Biol Chem, 2005) has revived this protease as a therapeutic target.

The Wolfe lab has also been actively investigating the structure, mechanism, and inhibition of other intramembrane proteases, such as the serine protease Rhomboid (Urban and Wolfe, Proc Natl Acad Sci USA, 2005) and the presenilin homolog signal peptide peptidase (Sato et al., Biochemistry, 2006; Narayanan et al., J Biol Chem, 2007), both of which are highly conserved across evolution and play critical roles in biology. The goal is to establish common biochemical principles and strategies for designing inhibitors for this new family of membrane-embedded enzymes.

The lab has also begun to combine chemistry and biology toward the study of another factor critical to the pathogenesis of dementias: the microtubule-associated protein tau. Filaments of tau are a common feature in a variety of different neurodegenerative diseases, including Alzheimer’s disease. Mutations in the gene encoding this protein are associated with dominant, familial forms of frontotemporal dementia, and many of these mutations alter pre-mRNA splicing to increase inclusion of exon 10. The Wolfe lab has recently validated the in vivo existence of a hypothetical stem loop at the end of exon 10, where many of the dementia-associated mutations occur (Donahue et al., J Biol Chem, 2006). These mutations destabilize this RNA stem loop structure, allowing more ready access to splicing factors. High-throughput screening has led to identification of small molecules that interact with and stabilize this structure (Donahue et al., J Biomol Screen, 2007), and efforts are ongoing to improve the potency and selectivity of these agents to provide new tools for chemical biology as well as new prototype therapeutics. In addition, the lab has studied alternative splicing of the beta-site APP-cleaving enzyme 1 (BACE1; beta-secretase), determining that alternative splice isoforms are catalytically inactive and that shunting BACE1 down these alternative pathways with antisense oligonucleotides effectively lowers amyloid beta-protein production in cells (Mowrer and Wolfe, J Biol Chem, 2008). Thus, modulation of BACE1 alternative splicing represents a new strategy for developing disease-modifying therapies for Alzheimer’s disease.

Dr. Wolfe is highly committed to graduate-level teaching at HMS. In 2003, he co-directed and taught a new quarter course, Neurobiology 300, “Biochemistry and Biology of Neurodegenerative Diseases”, a 2-hour-per-week class with some didactic presentation but primarily discussion of seminal and current research articles in the field. In 2005 and 2007, he directed and taught this course in its entirety. Each time it has been offered, the course has been very popular, received high praise from the students. Dr. Wolfe has also been involved in leading a discussion section of BCMP 201, “Proteins: Structure, Function, and Catalysis” from 2002-5; in 2006-8, he presented lectures on enzyme mechanisms and inhibition for this course. In 2004, he has also led a discussion section for Med Sci 300, the Conduct of Science, an ethics course required of all DMS graduate students.


 Mentoring 
 completed student projects
Construction of a Tau Minigene and Preliminary Analysis of Its Splicing
Summer, 06/11/07 - 08/03/07

 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Wolfe MS. Toward the structure of presenilin/?-secretase and presenilin homologs. Biochim Biophys Acta. 2013 Dec; 1828(12):2886-97.
    View in: PubMed
  2. Dickson JR, Kruse C, Montagna DR, Finsen B, Wolfe MS. Alternative polyadenylation and miR-34 family members regulate tau expression. J Neurochem. 2013 Dec; 127(6):739-49.
    View in: PubMed
  3. Wolfe MS. Alzheimer's ?-secretase under arrestin. Nat Med. 2013 Jan; 19(1):22-4.
    View in: PubMed
  4. Wolfe MS. Structural biology: Membrane enzyme cuts a fine figure. Nature. 2013 Jan 3; 493(7430):34-5.
    View in: PubMed
  5. Wolfe MS. The role of tau in neurodegenerative diseases and its potential as a therapeutic target. Scientifica (Cairo). 2012; 2012:796024.
    View in: PubMed
  6. Wolfe MS. Introduction to special issue on Alzheimer's disease. J Med Chem. 2012 Nov 8; 55(21):8977-8.
    View in: PubMed
  7. Wolfe MS. Processive proteolysis by ?-secretase and the mechanism of Alzheimer's disease. Biol Chem. 2012 Sep; 393(9):899-905.
    View in: PubMed
  8. Peacey E, Rodriguez L, Liu Y, Wolfe MS. Targeting a pre-mRNA structure with bipartite antisense molecules modulates tau alternative splicing. Nucleic Acids Res. 2012 Oct 1; 40(19):9836-49.
    View in: PubMed
  9. Holmes O, Paturi S, Ye W, Wolfe MS, Selkoe DJ. Effects of membrane lipids on the activity and processivity of purified ?-secretase. Biochemistry. 2012 May 1; 51(17):3565-75.
    View in: PubMed
  10. Fisette JF, Montagna DR, Mihailescu MR, Wolfe MS. A G-rich element forms a G-quadruplex and regulates BACE1 mRNA alternative splicing. J Neurochem. 2012 Jun; 121(5):763-73.
    View in: PubMed
  11. De Strooper B, Iwatsubo T, Wolfe MS. Presenilins and ?-Secretase: Structure, Function, and Role in Alzheimer Disease. Cold Spring Harb Perspect Med. 2012 Jan; 2(1):a006304.
    View in: PubMed
  12. Wolfe MS. ?-Secretase as a target for Alzheimer's disease. Adv Pharmacol. 2012; 64:127-53.
    View in: PubMed
  13. Wolfe MS. ?-Secretase inhibitors and modulators for Alzheimer's disease. J Neurochem. 2012 Jan; 120 Suppl 1:89-98.
    View in: PubMed
  14. Narayanan S, Arthanari H, Wolfe MS, Wagner G. Molecular characterization of disrupted in schizophrenia-1 risk variant S704C reveals the formation of altered oligomeric assembly. J Biol Chem. 2011 Dec 23; 286(51):44266-76.
    View in: PubMed
  15. Quintero-Monzon O, Martin MM, Fernandez MA, Cappello CA, Krzysiak AJ, Osenkowski P, Wolfe MS. Dissociation between the processivity and total activity of ?-secretase: implications for the mechanism of Alzheimer's disease-causing presenilin mutations. Biochemistry. 2011 Oct 25; 50(42):9023-35.
    View in: PubMed
  16. Wang X, Cowan JW, Gerhart M, Zelickson BR, Jiang J, He K, Wolfe MS, Black RA, Frank SJ. ?-Secretase-mediated growth hormone receptor proteolysis: mapping of the intramembranous cleavage site. Biochem Biophys Res Commun. 2011 May 13; 408(3):432-6.
    View in: PubMed
  17. Wolfe MS. Alzheimer's Disease Drug Discovery--11th International Conference--Promising New Therapeutic Approaches. 27-28 September 2010, Jersey City, NJ, USA. IDrugs. 2010 Dec; 13(12):825-7.
    View in: PubMed
  18. Wolfe MS. Alzheimer's Disease Drug Discovery--11th International Conference--Targeting Pathological Tau. 27-28 September 2010, Jersey City, NJ, USA. IDrugs. 2010 Dec; 13(12):828-9.
    View in: PubMed
  19. Lu JP, Zhang J, Kim K, Case TC, Matusik RJ, Chen YH, Wolfe M, Nopparat J, Lu Q. Human homolog of Drosophila Hairy and enhancer of split 1, Hes1, negatively regulates d-catenin (CTNND2) expression in cooperation with E2F1 in prostate cancer. Mol Cancer. 2010; 9:304.
    View in: PubMed
  20. Wolfe MS. Structure, mechanism and inhibition of gamma-secretase and presenilin-like proteases. Biol Chem. 2010 Aug; 391(8):839-47.
    View in: PubMed
  21. Wolfe MS, Selkoe DJ. Giving Alzheimer's the old one-two. Cell. 2010 Jul 23; 142(2):194-6.
    View in: PubMed
  22. Augelli-Szafran CE, Wei HX, Lu D, Zhang J, Gu Y, Yang T, Osenkowski P, Ye W, Wolfe MS. Discovery of notch-sparing gamma-secretase inhibitors. Curr Alzheimer Res. 2010 May; 7(3):207-9.
    View in: PubMed
  23. Lu Q, Ding K, Frosch MP, Jones S, Wolfe M, Xia W, Lanford GW. Alzheimer's disease-linked presenilin mutation (PS1M146L) induces filamin expression and ?-secretase independent redistribution. J Alzheimers Dis. 2010; 22(1):235-45.
    View in: PubMed
  24. Liu Y, Peacey E, Dickson J, Donahue CP, Zheng S, Varani G, Wolfe MS. Mitoxantrone analogues as ligands for a stem-loop structure of tau pre-mRNA. J Med Chem. 2009 Nov 12; 52(21):6523-6.
    View in: PubMed
  25. Zheng S, Chen Y, Donahue CP, Wolfe MS, Varani G. Structural basis for stabilization of the tau pre-mRNA splicing regulatory element by novantrone (mitoxantrone). Chem Biol. 2009 May 29; 16(5):557-66.
    View in: PubMed
  26. Wolfe MS. Intramembrane proteolysis. Chem Rev. 2009 Apr; 109(4):1599-612.
    View in: PubMed
  27. Li H, Wolfe MS, Selkoe DJ. Toward structural elucidation of the gamma-secretase complex. Structure. 2009 Mar 11; 17(3):326-34.
    View in: PubMed
  28. Mowrer KR, Wolfe MS. Identification of a cis-acting element involved in the regulation of BACE1 mRNA alternative splicing. J Neurochem. 2009 May; 109(4):1008-16.
    View in: PubMed
  29. Golde TE, Wolfe MS, Greenbaum DC. Signal peptide peptidases: a family of intramembrane-cleaving proteases that cleave type 2 transmembrane proteins. Semin Cell Dev Biol. 2009 Apr; 20(2):225-30.
    View in: PubMed
  30. Wolfe MS. Intramembrane-cleaving proteases. J Biol Chem. 2009 May 22; 284(21):13969-73.
    View in: PubMed
  31. Wolfe MS. gamma-Secretase in biology and medicine. Semin Cell Dev Biol. 2009 Apr; 20(2):219-24.
    View in: PubMed
  32. Wolfe MS. Selective amyloid-beta lowering agents. BMC Neurosci. 2008; 9 Suppl 2:S4.
    View in: PubMed
  33. Osenkowski P, Li H, Ye W, Li D, Aeschbach L, Fraering PC, Wolfe MS, Selkoe DJ, Li H. Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol. 2009 Jan 16; 385(2):642-52.
    View in: PubMed
  34. Wolfe MS. Tau mutations in neurodegenerative diseases. J Biol Chem. 2009 Mar 6; 284(10):6021-5.
    View in: PubMed
  35. Sato T, Ananda K, Cheng CI, Suh EJ, Narayanan S, Wolfe MS. Distinct pharmacological effects of inhibitors of signal peptide peptidase and gamma-secretase. J Biol Chem. 2008 Nov 28; 283(48):33287-95.
    View in: PubMed
  36. Wolfe MS. Inhibition and modulation of gamma-secretase for Alzheimer's disease. Neurotherapeutics. 2008 Jul; 5(3):391-8.
    View in: PubMed
  37. Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price RW, Moore B, Rangachari V, Cusack B, Eriksen J, Jansen-West K, Verbeeck C, Yager D, Eckman C, Ye W, Sagi S, Cottrell BA, Torpey J, Rosenberry TL, Fauq A, Wolfe MS, Schmidt B, Walsh DM, Koo EH, Golde TE. Substrate-targeting gamma-secretase modulators. Nature. 2008 Jun 12; 453(7197):925-9.
    View in: PubMed
  38. Osenkowski P, Ye W, Wang R, Wolfe MS, Selkoe DJ. Direct and potent regulation of gamma-secretase by its lipid microenvironment. J Biol Chem. 2008 Aug 15; 283(33):22529-40.
    View in: PubMed
  39. Mowrer KR, Wolfe MS. Promotion of BACE1 mRNA alternative splicing reduces amyloid beta-peptide production. J Biol Chem. 2008 Jul 4; 283(27):18694-701.
    View in: PubMed
  40. Wolfe MS. Gamma-secretase inhibition and modulation for Alzheimer's disease. Curr Alzheimer Res. 2008 Apr; 5(2):158-64.
    View in: PubMed
  41. Wolfe MS. Gamma-secretase: structure, function, and modulation for Alzheimer's disease. Curr Top Med Chem. 2008; 8(1):2-8.
    View in: PubMed
  42. Wolfe MS. gamma-Secretase modulators. Curr Alzheimer Res. 2007 Dec; 4(5):571-3.
    View in: PubMed
  43. Cacquevel M, Aeschbach L, Osenkowski P, Li D, Ye W, Wolfe MS, Li H, Selkoe DJ, Fraering PC. Rapid purification of active gamma-secretase, an intramembrane protease implicated in Alzheimer's disease. J Neurochem. 2008 Jan; 104(1):210-20.
    View in: PubMed
  44. Selkoe DJ, Wolfe MS. Presenilin: running with scissors in the membrane. Cell. 2007 Oct 19; 131(2):215-21.
    View in: PubMed
  45. Sato T, Diehl TS, Narayanan S, Funamoto S, Ihara Y, De Strooper B, Steiner H, Haass C, Wolfe MS. Active gamma-secretase complexes contain only one of each component. J Biol Chem. 2007 Nov 23; 282(47):33985-93.
    View in: PubMed
  46. Wolfe MS, Guénette SY. APP at a glance. J Cell Sci. 2007 Sep 15; 120(Pt 18):3157-61.
    View in: PubMed
  47. Donahue CP, Ni J, Rozners E, Glicksman MA, Wolfe MS. Identification of tau stem loop RNA stabilizers. J Biomol Screen. 2007 Sep; 12(6):789-99.
    View in: PubMed
  48. Narayanan S, Sato T, Wolfe MS. A C-terminal region of signal peptide peptidase defines a functional domain for intramembrane aspartic protease catalysis. J Biol Chem. 2007 Jul 13; 282(28):20172-9.
    View in: PubMed
  49. Lieberman RL, Wolfe MS. From rhomboid function to structure and back again. Proc Natl Acad Sci U S A. 2007 May 15; 104(20):8199-200.
    View in: PubMed
  50. Wolfe MS. When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007 Feb; 8(2):136-40.
    View in: PubMed
  51. Lieberman RL, Wolfe MS. Membrane-embedded protease poses for photoshoot. Proc Natl Acad Sci U S A. 2007 Jan 9; 104(2):401-2.
    View in: PubMed
  52. Wolfe MS. Alzheimer protease hitches a ride. Nat Med. 2006 Dec; 12(12):1352-4.
    View in: PubMed
  53. Sato T, Nyborg AC, Iwata N, Diehl TS, Saido TC, Golde TE, Wolfe MS. Signal peptide peptidase: biochemical properties and modulation by nonsteroidal antiinflammatory drugs. Biochemistry. 2006 Jul 18; 45(28):8649-56.
    View in: PubMed
  54. Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, Rodriguez CG, Sai H, Tobias J, Li Y, Wolfe MS, Shachaf C, Felsher D, Blacklow SC, Pear WS, Aster JC. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev. 2006 Aug 1; 20(15):2096-109.
    View in: PubMed
  55. Wolfe MS. The gamma-secretase complex: membrane-embedded proteolytic ensemble. Biochemistry. 2006 Jul 4; 45(26):7931-9.
    View in: PubMed
  56. Kornilova AY, Kim J, Laudon H, Wolfe MS. Deducing the transmembrane domain organization of presenilin-1 in gamma-secretase by cysteine disulfide cross-linking. Biochemistry. 2006 Jun 20; 45(24):7598-604.
    View in: PubMed
  57. Donahue CP, Muratore C, Wu JY, Kosik KS, Wolfe MS. Stabilization of the tau exon 10 stem loop alters pre-mRNA splicing. J Biol Chem. 2006 Aug 18; 281(33):23302-6.
    View in: PubMed
  58. Wolfe MS. Shutting down Alzheimer's. Sci Am. 2006 May; 294(5):72-9.
    View in: PubMed
  59. Lazarov VK, Fraering PC, Ye W, Wolfe MS, Selkoe DJ, Li H. Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci U S A. 2006 May 2; 103(18):6889-94.
    View in: PubMed
  60. Fraering PC, Ye W, LaVoie MJ, Ostaszewski BL, Selkoe DJ, Wolfe MS. gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site. J Biol Chem. 2005 Dec 23; 280(51):41987-96.
    View in: PubMed
  61. George JE, Ahmad Y, Varghai D, Li X, Berlin J, Jackowe D, Jungermann M, Wolfe MS, Lilge L, Totonchi A, Morris RL, Peterson A, Lust WD, Kenney ME, Hoppel CL, Sun J, Oleinick NL, Dean D. Pc 4 photodynamic therapy of U87-derived human glioma in the nude rat. Lasers Surg Med. 2005 Jun; 36(5):383-9.
    View in: PubMed
  62. Dean D, Wolfe MS, Ahmad Y, Totonchi A, Chen JE, Fisher JP, Cooke MN, Rimnac CM, Lennon DP, Caplan AI, Topham NS, Mikos AG. Effect of transforming growth factor beta 2 on marrow-infused foam poly(propylene fumarate) tissue-engineered constructs for the repair of critical-size cranial defects in rabbits. Tissue Eng. 2005 May-Jun; 11(5-6):923-39.
    View in: PubMed
  63. Foulkes AS, Reilly M, Zhou L, Wolfe M, Rader DJ. Mixed modelling to characterize genotype-phenotype associations. Stat Med. 2005 Mar 15; 24(5):775-89.
    View in: PubMed
  64. Cowan JW, Wang X, Guan R, He K, Jiang J, Baumann G, Black RA, Wolfe MS, Frank SJ. Growth hormone receptor is a target for presenilin-dependent gamma-secretase cleavage. J Biol Chem. 2005 May 13; 280(19):19331-42.
    View in: PubMed
  65. Kornilova AY, Bihel F, Das C, Wolfe MS. The initial substrate-binding site of gamma-secretase is located on presenilin near the active site. Proc Natl Acad Sci U S A. 2005 Mar 1; 102(9):3230-5.
    View in: PubMed
  66. Bernardos RL, Lentz SI, Wolfe MS, Raymond PA. Notch-Delta signaling is required for spatial patterning and Müller glia differentiation in the zebrafish retina. Dev Biol. 2005 Feb 15; 278(2):381-95.
    View in: PubMed
  67. Bakshi P, Liao YF, Gao J, Ni J, Stein R, Yeh LA, Wolfe MS. A high-throughput screen to identify inhibitors of amyloid beta-protein precursor processing. J Biomol Screen. 2005 Feb; 10(1):1-12.
    View in: PubMed
  68. Urban S, Wolfe MS. Reconstitution of intramembrane proteolysis in vitro reveals that pure rhomboid is sufficient for catalysis and specificity. Proc Natl Acad Sci U S A. 2005 Feb 8; 102(6):1883-8.
    View in: PubMed
  69. Laras Y, Quéléver G, Garino C, Pietrancosta N, Sheha M, Bihel F, Wolfe MS, Kraus JL. Substituted thiazolamide coupled to a redox delivery system: a new gamma-secretase inhibitor with enhanced pharmacokinetic profile. Org Biomol Chem. 2005 Feb 21; 3(4):612-8.
    View in: PubMed
  70. Bakshi P, Wolfe MS. Stereochemical analysis of (hydroxyethyl)urea peptidomimetic inhibitors of gamma-secretase. J Med Chem. 2004 Dec 16; 47(26):6485-9.
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  71. Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS. Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem. 2004 Nov 19; 279(47):49523-32.
    View in: PubMed
  72. Wolfe MS, Kopan R. Intramembrane proteolysis: theme and variations. Science. 2004 Aug 20; 305(5687):1119-23.
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  73. Fraering PC, Ye W, Strub JM, Dolios G, LaVoie MJ, Ostaszewski BL, van Dorsselaer A, Wang R, Selkoe DJ, Wolfe MS. Purification and characterization of the human gamma-secretase complex. Biochemistry. 2004 Aug 3; 43(30):9774-89.
    View in: PubMed
  74. Bihel F, Das C, Bowman MJ, Wolfe MS. Discovery of a Subnanomolar helical D-tridecapeptide inhibitor of gamma-secretase. J Med Chem. 2004 Jul 29; 47(16):3931-3.
    View in: PubMed
  75. van den Brandt J, Voss K, Schott M, Hünig T, Wolfe MS, Reichardt HM. Inhibition of Notch signaling biases rat thymocyte development towards the NK cell lineage. Eur J Immunol. 2004 May; 34(5):1405-13.
    View in: PubMed
  76. Esler WP, Das C, Wolfe MS. Probing pockets S2-S4' of the gamma-secretase active site with (hydroxyethyl)urea peptidomimetics. Bioorg Med Chem Lett. 2004 Apr 19; 14(8):1935-8.
    View in: PubMed
  77. Eagar TN, Tang Q, Wolfe M, He Y, Pear WS, Bluestone JA. Notch 1 signaling regulates peripheral T cell activation. Immunity. 2004 Apr; 20(4):407-15.
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  78. Dowthwaite GP, Bishop JC, Redman SN, Khan IM, Rooney P, Evans DJ, Haughton L, Bayram Z, Boyer S, Thomson B, Wolfe MS, Archer CW. The surface of articular cartilage contains a progenitor cell population. J Cell Sci. 2004 Feb 29; 117(Pt 6):889-97.
    View in: PubMed
  79. Fraering PC, LaVoie MJ, Ye W, Ostaszewski BL, Kimberly WT, Selkoe DJ, Wolfe MS. 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. Biochemistry. 2004 Jan 20; 43(2):323-33.
    View in: PubMed
  80. Nyborg AC, Kornilova AY, Jansen K, Ladd TB, Wolfe MS, Golde TE. Signal peptide peptidase forms a homodimer that is labeled by an active site-directed gamma-secretase inhibitor. J Biol Chem. 2004 Apr 9; 279(15):15153-60.
    View in: PubMed
  81. Kimberly WT, Wolfe MS. Identity and function of gamma-secretase. J Neurosci Res. 2003 Nov 1; 74(3):353-60.
    View in: PubMed
  82. Baulac S, LaVoie MJ, Kimberly WT, Strahle J, Wolfe MS, Selkoe DJ, Xia W. Functional gamma-secretase complex assembly in Golgi/trans-Golgi network: interactions among presenilin, nicastrin, Aph1, Pen-2, and gamma-secretase substrates. Neurobiol Dis. 2003 Nov; 14(2):194-204.
    View in: PubMed
  83. Schroeter EH, Ilagan MX, Brunkan AL, Hecimovic S, Li YM, Xu M, Lewis HD, Saxena MT, De Strooper B, Coonrod A, Tomita T, Iwatsubo T, Moore CL, Goate A, Wolfe MS, Shearman M, Kopan R. A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc Natl Acad Sci U S A. 2003 Oct 28; 100(22):13075-80.
    View in: PubMed
  84. Das C, Berezovska O, Diehl TS, Genet C, Buldyrev I, Tsai JY, Hyman BT, Wolfe MS. Designed helical peptides inhibit an intramembrane protease. J Am Chem Soc. 2003 Oct 1; 125(39):11794-5.
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  85. Adler SH, Chiffoleau E, Xu L, Dalton NM, Burg JM, Wells AD, Wolfe MS, Turka LA, Pear WS. Notch signaling augments T cell responsiveness by enhancing CD25 expression. J Immunol. 2003 Sep 15; 171(6):2896-903.
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  86. Xia W, Wolfe MS. Intramembrane proteolysis by presenilin and presenilin-like proteases. J Cell Sci. 2003 Jul 15; 116(Pt 14):2839-44.
    View in: PubMed
  87. LaVoie MJ, Fraering PC, Ostaszewski BL, Ye W, Kimberly WT, Wolfe MS, Selkoe DJ. Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrin. J Biol Chem. 2003 Sep 26; 278(39):37213-22.
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  88. Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell. 2003 Jun; 3(6):565-76.
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  89. Berezovska O, Ramdya P, Skoch J, Wolfe MS, Bacskai BJ, Hyman BT. Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging. J Neurosci. 2003 Jun 1; 23(11):4560-6.
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  90. Campbell WA, Reed ML, Strahle J, Wolfe MS, Xia W. Presenilin endoproteolysis mediated by an aspartyl protease activity pharmacologically distinct from gamma-secretase. J Neurochem. 2003 Jun; 85(6):1563-74.
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  91. Dean D, Topham NS, Meneghetti SC, Wolfe MS, Jepsen K, He S, Chen JE, Fisher JP, Cooke M, Rimnac C, Mikos AG. Poly(propylene fumarate) and poly(DL-lactic-co-glycolic acid) as scaffold materials for solid and foam-coated composite tissue-engineered constructs for cranial reconstruction. Tissue Eng. 2003 Jun; 9(3):495-504.
    View in: PubMed
  92. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A. 2003 May 27; 100(11):6382-7.
    View in: PubMed
  93. Wolfe MS. Gamma-secretase--intramembrane protease with a complex. Sci Aging Knowledge Environ. 2003 Mar 19; 2003(11):PE7.
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  94. Kornilova AY, Das C, Wolfe MS. Differential effects of inhibitors on the gamma-secretase complex. Mechanistic implications. J Biol Chem. 2003 May 9; 278(19):16470-3.
    View in: PubMed
  95. Kimberly WT, Esler WP, Ye W, Ostaszewski BL, Gao J, Diehl T, Selkoe DJ, Wolfe MS. Notch and the amyloid precursor protein are cleaved by similar gamma-secretase(s). Biochemistry. 2003 Jan 14; 42(1):137-44.
    View in: PubMed
  96. Wolfe MS. The secretases of Alzheimer's disease. Curr Top Dev Biol. 2003; 54:233-61.
    View in: PubMed
  97. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, Aster JC. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol. 2003 Jan; 23(2):655-64.
    View in: PubMed
  98. Wolfe MS. APP, Notch, and presenilin: molecular pieces in the puzzle of Alzheimer's disease. Int Immunopharmacol. 2002 Dec; 2(13-14):1919-29.
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  99. Micchelli CA, Esler WP, Kimberly WT, Jack C, Berezovska O, Kornilova A, Hyman BT, Perrimon N, Wolfe MS. Gamma-secretase/presenilin inhibitors for Alzheimer's disease phenocopy Notch mutations in Drosophila. FASEB J. 2003 Jan; 17(1):79-81.
    View in: PubMed
  100. Wolfe MS. Therapeutic strategies for Alzheimer's disease. Nat Rev Drug Discov. 2002 Nov; 1(11):859-66.
    View in: PubMed
  101. Wolfe MS, Esler WP, Das C. Continuing strategies for inhibiting Alzheimer's gamma-secretase. J Mol Neurosci. 2002 Aug-Oct; 19(1-2):83-7.
    View in: PubMed
  102. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ. Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulation. J Biol Chem. 2002 Sep 20; 277(38):35113-7.
    View in: PubMed
  103. Wolfe MS, Dean D, Chen JE, Fisher JP, Han S, Rimnac CM, Mikos AG. In vitro degradation and fracture toughness of multilayered porous poly(propylene fumarate)/beta-tricalcium phosphate scaffolds. J Biomed Mater Res. 2002 Jul; 61(1):159-64.
    View in: PubMed
  104. Wolfe MS, Selkoe DJ. Biochemistry. Intramembrane proteases--mixing oil and water. Science. 2002 Jun 21; 296(5576):2156-7.
    View in: PubMed
  105. Tsai JY, Wolfe MS, Xia W. The search for gamma-secretase and development of inhibitors. Curr Med Chem. 2002 Jun; 9(11):1087-106.
    View in: PubMed
  106. Esler WP, Das C, Campbell WA, Kimberly WT, Kornilova AY, Diehl TS, Ye W, Ostaszewski BL, Xia W, Selkoe DJ, Wolfe MS. Amyloid-lowering isocoumarins are not direct inhibitors of gamma-secretase. Nat Cell Biol. 2002 May; 4(5):E110-1; author reply E111-2.
    View in: PubMed
  107. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4; 416(6880):535-9.
    View in: PubMed
  108. Wolfe MS. Secretase as a target for Alzheimer's disease. Curr Top Med Chem. 2002 Apr; 2(4):371-83.
    View in: PubMed
  109. Leissring MA, Murphy MP, Mead TR, Akbari Y, Sugarman MC, Jannatipour M, Anliker B, Müller U, Saftig P, De Strooper B, Wolfe MS, Golde TE, LaFerla FM. A physiologic signaling role for the gamma -secretase-derived intracellular fragment of APP. Proc Natl Acad Sci U S A. 2002 Apr 2; 99(7):4697-702.
    View in: PubMed
  110. Esler WP, Kimberly WT, Ostaszewski BL, Ye W, Diehl TS, Selkoe DJ, Wolfe MS. Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrate. Proc Natl Acad Sci U S A. 2002 Mar 5; 99(5):2720-5.
    View in: PubMed
  111. Zhang J, Ye W, Wang R, Wolfe MS, Greenberg BD, Selkoe DJ. Proteolysis of chimeric beta-amyloid precursor proteins containing the Notch transmembrane domain yields amyloid beta-like peptides. J Biol Chem. 2002 Apr 26; 277(17):15069-75.
    View in: PubMed
  112. Wolfe MS. gamma-Secretase inhibitors as molecular probes of presenilin function. J Mol Neurosci. 2001 Oct; 17(2):199-204.
    View in: PubMed
  113. Esler WP, Wolfe MS. A portrait of Alzheimer secretases--new features and familiar faces. Science. 2001 Aug 24; 293(5534):1449-54.
    View in: PubMed
  114. Wolfe MS. Secretase targets for Alzheimer's disease: identification and therapeutic potential. J Med Chem. 2001 Jun 21; 44(13):2039-60.
    View in: PubMed
  115. Hadland BK, Manley NR, Su D, Longmore GD, Moore CL, Wolfe MS, Schroeter EH, Kopan R. Gamma -secretase inhibitors repress thymocyte development. Proc Natl Acad Sci U S A. 2001 Jun 19; 98(13):7487-91.
    View in: PubMed
  116. Jack C, Berezovska O, Wolfe MS, Hyman BT. Effect of PS1 deficiency and an APP gamma-secretase inhibitor on Notch1 signaling in primary mammalian neurons. Brain Res Mol Brain Res. 2001 Mar 5; 87(2):166-74.
    View in: PubMed
  117. Wolfe MS. Presenilin and gamma-secretase: structure meets function. J Neurochem. 2001 Mar; 76(6):1615-20.
    View in: PubMed
  118. Wolfe MS, Haass C. The Role of presenilins in gamma-secretase activity. J Biol Chem. 2001 Feb 23; 276(8):5413-6.
    View in: PubMed
  119. Xia W, Ostaszewski BL, Kimberly WT, Rahmati T, Moore CL, Wolfe MS, Selkoe DJ. FAD mutations in presenilin-1 or amyloid precursor protein decrease the efficacy of a gamma-secretase inhibitor: evidence for direct involvement of PS1 in the gamma-secretase cleavage complex. Neurobiol Dis. 2000 Dec; 7(6 Pt B):673-81.
    View in: PubMed
  120. Moore CL, Leatherwood DD, Diehl TS, Selkoe DJ, Wolfe MS. Difluoro ketone peptidomimetics suggest a large S1 pocket for Alzheimer's gamma-secretase: implications for inhibitor design. J Med Chem. 2000 Sep 7; 43(18):3434-42.
    View in: PubMed
  121. Johnson JA, Herring VL, Wolfe MS, Relling MV. CYP1A2 and CYP2D6 4-hydroxylate propranolol and both reactions exhibit racial differences. J Pharmacol Exp Ther. 2000 Sep; 294(3):1099-105.
    View in: PubMed
  122. Berezovska O, Jack C, McLean P, Aster JC, Hicks C, Xia W, Wolfe MS, Kimberly WT, Weinmaster G, Selkoe DJ, Hyman BT. Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling. J Neurochem. 2000 Aug; 75(2):583-93.
    View in: PubMed
  123. Xia W, Ray WJ, Ostaszewski BL, Rahmati T, Kimberly WT, Wolfe MS, Zhang J, Goate AM, Selkoe DJ. Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta-protein generation. Proc Natl Acad Sci U S A. 2000 Aug 1; 97(16):9299-304.
    View in: PubMed
  124. Esler WP, Kimberly WT, Ostaszewski BL, Diehl TS, Moore CL, Tsai JY, Rahmati T, Xia W, Selkoe DJ, Wolfe MS. Transition-state analogue inhibitors of gamma-secretase bind directly to presenilin-1. Nat Cell Biol. 2000 Jul; 2(7):428-34.
    View in: PubMed
  125. Johnson JA, Akers WS, Herring VL, Wolfe MS, Sullivan JM. Gender differences in labetalol kinetics: importance of determining stereoisomer kinetics for racemic drugs. Pharmacotherapy. 2000 Jun; 20(6):622-8.
    View in: PubMed
  126. Selkoe DJ, Wolfe MS. In search of gamma-secretase: presenilin at the cutting edge. Proc Natl Acad Sci U S A. 2000 May 23; 97(11):5690-2.
    View in: PubMed
  127. Kimberly WT, Xia W, Rahmati T, Wolfe MS, Selkoe DJ. The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. J Biol Chem. 2000 Feb 4; 275(5):3173-8.
    View in: PubMed
  128. Moore CL, Diehl TS, Selkoe DJ, Wolfe MS. Toward the characterization and identification of gamma-secretases using transition-state analogue inhibitors. Ann N Y Acad Sci. 2000; 920:197-205.
    View in: PubMed
  129. Berezovska O, Jack C, McLean P, Aster JC, Hicks C, Xia W, Wolfe MS, Weinmaster G, Selkoe DJ, Hyman BT. Rapid Notch1 nuclear translocation after ligand binding depends on presenilin-associated gamma-secretase activity. Ann N Y Acad Sci. 2000; 920:223-6.
    View in: PubMed
  130. Ray WJ, Yao M, Mumm J, Schroeter EH, Saftig P, Wolfe M, Selkoe DJ, Kopan R, Goate AM. Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch. J Biol Chem. 1999 Dec 17; 274(51):36801-7.
    View in: PubMed
  131. Wolfe MS, De Los Angeles J, Miller DD, Xia W, Selkoe DJ. Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease. Biochemistry. 1999 Aug 31; 38(35):11223-30.
    View in: PubMed
  132. Wolfe MS, Xia W, Moore CL, Leatherwood DD, Ostaszewski B, Rahmati T, Donkor IO, Selkoe DJ. Peptidomimetic probes and molecular modeling suggest that Alzheimer's gamma-secretase is an intramembrane-cleaving aspartyl protease. Biochemistry. 1999 Apr 13; 38(15):4720-7.
    View in: PubMed
  133. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999 Apr 8; 398(6727):518-22.
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  134. Wolfe MS, Xia W, Ostaszewski BL, Diehl TS, Kimberly WT, Selkoe DJ. Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity. Nature. 1999 Apr 8; 398(6727):513-7.
    View in: PubMed
  135. Wolfe MS, Citron M, Diehl TS, Xia W, Donkor IO, Selkoe DJ. A substrate-based difluoro ketone selectively inhibits Alzheimer's gamma-secretase activity. J Med Chem. 1998 Jan 1; 41(1):6-9.
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  136. Wolfe MS, Klein L. Sex differences in absolute rates of bone resorption in young rats: appendicular versus axial bones. Calcif Tissue Int. 1996 Jul; 59(1):51-7.
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  137. Klein L, Lemel MS, Wolfe MS, Shaffer J. Cyclosporin A does not affect the absolute rate of cortical bone resorption at the organ level in the growing rat. Calcif Tissue Int. 1994 Oct; 55(4):295-301.
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  138. Wolfe MS, Lee Y, Bartlett WJ, Borcherding DR, Borchardt RT. 4'-modified analogues of aristeromycin and neplanocin A: synthesis and inhibitory activity toward S-adenosyl-L-homocysteine hydrolase. J Med Chem. 1992 May 15; 35(10):1782-91.
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  139. Nguyen TD, Wolfe MS, Heintz GG, Whitcomb DC, Taylor IL. High affinity binding proteins for pancreatic polypeptide on rat liver membranes. J Biol Chem. 1992 May 5; 267(13):9416-21.
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  140. Wolfe MS, Borchardt RT. S-adenosyl-L-homocysteine hydrolase as a target for antiviral chemotherapy. J Med Chem. 1991 May; 34(5):1521-30.
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  141. Paisley SD, Wolfe MS, Borchardt RT. Oxidation of neplanocin A to the corresponding 3'-keto derivative by S-adenosylhomocysteine hydrolase. J Med Chem. 1989 Jul; 32(7):1415-8.
    View in: PubMed
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