Dennis Selkoe

Summary

Affiliation: Harvard University
Country: USA

Publications

  1. 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
  2. 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
  3. pmc α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation
    Tim Bartels
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 477:107-10. 2011
  4. pmc Deciphering Alzheimer disease
    Dennis Selkoe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Cold Spring Harb Perspect Med 2:a011460. 2012
  5. ncbi request reprint Preventing Alzheimer's disease
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Science 337:1488-92. 2012
  6. pmc Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1
    Tracy L Young-Pearse
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Neural Dev 3:15. 2008
  7. pmc Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation
    Richard C Davis
    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523 1870, USA
    Mol Neurodegener 6:10. 2011
  8. ncbi request reprint Deciphering the molecular basis of memory failure in Alzheimer's disease
    Dominic M Walsh
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Neuron 44:181-93. 2004
  9. ncbi request reprint Developing preventive therapies for chronic diseases: lessons learned from Alzheimer's disease
    Dennis J Selkoe
    Harvard Medical School, Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Nutr Rev 65:S239-43. 2007
  10. ncbi request reprint Folding proteins in fatal ways
    Dennis J Selkoe
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Nature 426:900-4. 2003

Detail Information

Publications88

  1. 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
    ....
  2. 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...
  3. pmc α-Synuclein occurs physiologically as a helically folded tetramer that resists aggregation
    Tim Bartels
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 477:107-10. 2011
    ....
  4. pmc Deciphering Alzheimer disease
    Dennis Selkoe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Cold Spring Harb Perspect Med 2:a011460. 2012
    ..Alzheimer disease represents an insidious impairment of intellect and emotional well-being. However, recent advances in biochemical pathology and human genetics offer promise that effective therapeutic agents may soon be developed...
  5. ncbi request reprint Preventing Alzheimer's disease
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Science 337:1488-92. 2012
    ..This process will likely position the field for success, but only with much greater investment in all aspects of Alzheimer research and with careful design of future trials...
  6. pmc Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1
    Tracy L Young-Pearse
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Neural Dev 3:15. 2008
    ....
  7. pmc Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation
    Richard C Davis
    Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523 1870, USA
    Mol Neurodegener 6:10. 2011
    ..abstract:..
  8. ncbi request reprint Deciphering the molecular basis of memory failure in Alzheimer's disease
    Dominic M Walsh
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Neuron 44:181-93. 2004
    ..Accordingly, attempts to slow memory and cognitive loss by decreasing cerebral Abeta levels have entered human trials...
  9. ncbi request reprint Developing preventive therapies for chronic diseases: lessons learned from Alzheimer's disease
    Dennis J Selkoe
    Harvard Medical School, Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Nutr Rev 65:S239-43. 2007
    ..While hard work lies ahead, the movement from basic research to the clinic in AD represents a triumph of reductionist biology applied to the most complex of all biological systems, the human cerebral cortex...
  10. ncbi request reprint Folding proteins in fatal ways
    Dennis J Selkoe
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Nature 426:900-4. 2003
    ..Understanding some of the principles of protein folding has helped to explain how such diseases arise, with attendant therapeutic insights...
  11. ncbi request reprint Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration
    Dennis Selkoe
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
    Annu Rev Neurosci 26:565-97. 2003
    ..Elucidating the detailed mechanism of Presenilin processing of membrane proteins is important for understanding diverse signal transduction pathways and potentially for treating and preventing Alzheimer's disease...
  12. 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...
  13. pmc Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations
    Nina E Shepardson
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, HIM Room 730, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
    Arch Neurol 68:1385-92. 2011
    ....
  14. ncbi request reprint Amyloid beta-peptide is produced by cultured cells during normal metabolism: a reprise
    Dennis J Selkoe
    Center for Neurologic Diseases, Harvard Institutes of Medicine, Rm 730, 77 Avenue Louis Pasteur, Boston MA 02115, USA
    J Alzheimers Dis 9:163-8. 2006
    ..Here, I review the background underlying this discovery and then discuss its implications for research on Alzheimer's disease, particularly for the development of disease-modifying therapies...
  15. ncbi request reprint Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics
    Dennis J Selkoe
    Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Annu Rev Pharmacol Toxicol 43:545-84. 2003
    ....
  16. ncbi request reprint The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragments
    Matthew J LaVoie
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02215, USA
    J Biol Chem 278:34427-37. 2003
    ..Thus, Notch and its cognate ligands are processed by the same molecular machinery and may antagonistically regulate each other's signaling...
  17. pmc Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
    Ganesh M Shankar
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA
    Nat Med 14:837-42. 2008
    ..We conclude that soluble Abeta oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species...
  18. ncbi request reprint Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathies
    Ronit Sharon
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Biol Chem 278:49874-81. 2003
    ..Together with our earlier observations, these results suggest that alphaS-PUFA interactions help regulate neuronal PUFA levels as well as the oligomerization state of alphaS, both normally and in human synucleinopathies...
  19. ncbi request reprint A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference
    Tracy L Young-Pearse
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 27:14459-69. 2007
    ..We conclude that full-length APP functions as an important factor for proper migration of neuronal precursors into the cortical plate during the development of the mammalian brain...
  20. pmc Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer disease
    Matthew L Hemming
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS Med 4:e262. 2007
    ..The objective of this study was to determine if enhancing the clearance of Abeta in the brain by ex vivo gene delivery of an Abeta-degrading protease can reduce amyloid plaque burden...
  21. ncbi request reprint Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage
    Jay H Chyung
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 280:4383-92. 2005
    ....
  22. ncbi request reprint The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease
    Ronit Sharon
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, Boston, MA 02215, USA
    Neuron 37:583-95. 2003
    ..We conclude that alpha S interacts with PUFAs in vivo to promote the formation of highly soluble oligomers that precede the insoluble alpha S aggregates associated with neurodegeneration...
  23. ncbi request reprint gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins
    Dominic M Walsh
    Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Biochemistry 42:6664-73. 2003
    ....
  24. ncbi request reprint Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers
    Matthew Townsend
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA, USA
    Ann Neurol 60:668-76. 2006
    ..A particularly attractive therapeutic strategy is to selectively neutralize small, soluble Abeta oligomers that have recently been shown to mediate synaptic dysfunction...
  25. 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)...
  26. pmc Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein
    Wesley Farris
    Department of Neurology, Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Am J Pathol 164:1425-34. 2004
    ..Our findings have relevance for the emerging genetic evidence suggesting that IDE may be a late-onset AD-risk gene, and for the epidemiological relationships among hyperinsulinemia, DM2, and AD...
  27. 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...
  28. pmc Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial trafficking
    Andreas Weihofen
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Biochemistry 48:2045-52. 2009
    ..Finally, we find that Miro and Milton expression suppresses altered mitochondrial morphology induced by loss of Pink1 function in cell culture. Our findings suggest that Pink1 functions in the trafficking of mitochondria in cells...
  29. pmc Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease
    Matthew L Hemming
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Neurobiol Dis 26:273-81. 2007
    ..Furthermore, we find no change in plaque deposition or in peripheral Abeta levels. Data from these Alzheimer models suggest that captopril and similar ACE inhibitors do not cause Abeta accumulation in vivo...
  30. ncbi request reprint Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1
    Andreas Weihofen
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Hum Mol Genet 17:602-16. 2008
    ..Finally, we document the influence of Parkin on Pink1 subcellular distribution, providing further evidence for a common pathogenic pathway in recessive PD...
  31. ncbi request reprint Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid beta-protein at the cell surface
    Jay H Chyung
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 278:51035-43. 2003
    ..Our findings are consistent with a role for the gamma-secretase complex in the processing of numerous single-transmembrane receptors at the cell surface...
  32. pmc Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers
    Matthew Townsend
    Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, MA 02115, USA
    J Physiol 572:477-92. 2006
    ..We conclude that specific assemblies, particularly timers, of naturally secreted Abeta oligomers are potent and selective inhibitors of certain forms of hippocampal LTP...
  33. pmc Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates
    Allen C Chen
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 285:11378-91. 2010
    ..Taken together, our data suggest a dominant role for Aph-1 in interacting with gamma-secretase substrates prior to their processing by the proteolytic complex...
  34. pmc Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer disease
    Alon Monsonego
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Clin Invest 112:415-22. 2003
    ....
  35. ncbi request reprint Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway
    Ganesh M Shankar
    Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 27:2866-75. 2007
    ..Our approach provides a quantitative cellular model for elucidating the molecular basis of Abeta-induced neuronal dysfunction...
  36. 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
    ....
  37. ncbi request reprint Toward a remembrance of things past: deciphering Alzheimer disease
    Dennis J Selkoe
    Department of Neurology, Harvard Medical School, USA
    Harvey Lect 99:23-45. 2003
  38. pmc A profile of impaired insulin degradation in relation to late-life cognitive decline: a preliminary investigation
    Olivia I Okereke
    Division of Aging, Department of Medicine, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Int J Geriatr Psychiatry 24:177-82. 2009
    ..In preliminary analyses, we considered the relation of combined lower insulin secretion (c-peptide) and higher insulin--possibly a phenotype for impaired insulin degradation--to cognitive decline...
  39. pmc Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo
    Wesley Farris
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 100:4162-7. 2003
    ....
  40. doi request reprint HLA-DR alleles in amyloid beta-peptide autoimmunity: a highly immunogenic role for the DRB1*1501 allele
    Victor Zota
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA, USA
    J Immunol 183:3522-30. 2009
    ..This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Abeta-reactive T cells and Abeta immunogenicity among humans...
  41. ncbi request reprint Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway
    Matthew Townsend
    Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Biol Chem 282:33305-12. 2007
    ....
  42. pmc Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy
    Wesley Farris
    Center for Neurologic Diseases, Department of Neurology, Harvard Institutes of Medicine, Room 730, Boston, MA 02115, USA
    Am J Pathol 171:241-51. 2007
    ....
  43. pmc Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical development
    Tracy L Young-Pearse
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Neurosci 30:10431-40. 2010
    ....
  44. ncbi request reprint Alzheimer's disease is a synaptic failure
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, and the Harvard Center for Neurodegeneration and Repair, Boston, MA 02115, USA
    Science 298:789-91. 2002
    ....
  45. pmc Functional alterations in memory networks in early Alzheimer's disease
    Reisa A Sperling
    Department of Neurology, Center for Alzheimer s Research and Treatment, Brigham and Women s Hospital, 221 Longwood Avenue, Boston, MA 02115, USA
    Neuromolecular Med 12:27-43. 2010
    ..Research is ongoing to determine if these early network alterations will serve as sensitive predictors of clinical decline, and eventually, as markers of pharmacological response to potential disease-modifying treatments for AD...
  46. pmc Ten-year change in plasma amyloid beta levels and late-life cognitive decline
    Olivia I Okereke
    Division of Aging and Channing Laboratory, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, 181 Longwood Ave, Third Floor, Boston, MA 02115, USA
    Arch Neurol 66:1247-53. 2009
    ..Plasma levels of amyloid beta peptide (Abeta) are potential biomarkers of early cognitive impairment and decline and of Alzheimer disease risk...
  47. pmc Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Behav Brain Res 192:106-13. 2008
    ..A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging...
  48. pmc A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease
    Weiming Xia
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, HIM 616, 77 Ave Louis Pasteur, Boston, MA 02115, USA
    Arch Neurol 66:190-9. 2009
    ....
  49. pmc Performance characteristics of plasma amyloid-beta 40 and 42 assays
    Olivia I Okereke
    Division of Aging, Department of Medicine, Brigham and Women s Hospital, and Harvard Medical School, Boston, MA 02115, USA
    J Alzheimers Dis 16:277-85. 2009
    ..While these preliminary findings suggest that measuring plasma Abeta(40) and Abeta(42) may be feasible in varied research settings, additional work in this area is necessary...
  50. pmc Amyloid deposition is associated with impaired default network function in older persons without dementia
    Reisa A Sperling
    Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Neuron 63:178-88. 2009
    ....
  51. ncbi request reprint Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP mice
    Cynthia A Lemere
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Neurobiol Dis 14:10-8. 2003
    ..Most of the Abeta in the serum of the immunized mice was bound to antibodies. We conclude that following active immunization, anti-Abeta antibodies sequester serum Abeta and may increase central nervous system to serum Abeta clearance...
  52. pmc Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodies
    Michael G Schlossmacher
    Department of Neurology, Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Am J Pathol 160:1655-67. 2002
    ..These results suggest that functional parkin proteins may be required during LB formation...
  53. 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
  54. pmc Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervet
    Cynthia A Lemere
    Center for Neurologic Diseases, HIM 622, Department of Neurology, Brigham and Women s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02215, USA
    Am J Pathol 165:283-97. 2004
    ..The findings further support Abeta immunotherapy as a potential prevention and treatment of AD...
  55. ncbi request reprint Deciphering the genetic basis of Alzheimer's disease
    Dennis J Selkoe
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    Annu Rev Genomics Hum Genet 3:67-99. 2002
    ..This understanding of the genotype-to-phenotype conversions of familial AD has led to the development of pharmacological strategies to lower amyloid beta-protein levels as a way of treating or preventing all forms of the disease...
  56. ncbi request reprint Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death
    Malcolm A Leissring
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Harvard Medical School, Boston, MA 02115, USA
    Neuron 40:1087-93. 2003
    ..Our findings demonstrate that chronic upregulation of Abeta-degrading proteases represents an efficacious therapeutic approach to combating Alzheimer-type pathology in vivo...
  57. ncbi request reprint Aging, amyloid, and Alzheimer's disease: a perspective in honor of Carl Cotman
    Dennis J Selkoe
    Center for Neurological Diseases, Brigham and Women s Hospital, and the Harvard Center for Neurodegeneration and Repair Boston, Massachusetts, USA
    Neurochem Res 28:1705-13. 2003
    ..Some of these are now reaching the clinic, providing the final and most important test for this hypothetical mechanism of disease...
  58. pmc Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease
    Dennis J Selkoe
    Center for Neurologic Diseases, Harvard Medical School, Brigham and Women s Hospital, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA
    J Clin Invest 110:1375-81. 2002
  59. ncbi request reprint Introducing transglutaminase into the study of Alzheimer's disease. A personal look back
    Dennis J Selkoe
    Center for Neurologic Diseases, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, HIM 730, Boston, MA 02115, USA
    Neurochem Int 40:13-6. 2002
  60. ncbi request reprint Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseases
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Nat Cell Biol 6:1054-61. 2004
    ..A common theme has arisen in this field: normally-soluble proteins accumulate, misfold and oligomerize, inducing cytotoxic effects that are particularly devastating in the post-mitotic milieu of the neuron...
  61. ncbi request reprint Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation
    Dominic M Walsh
    Department of Neurology, Harvard Medical School, and Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115 5716, USA
    J Neurosci 25:2455-62. 2005
    ....
  62. 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...
  63. ncbi request reprint Dopamine covalently modifies and functionally inactivates parkin
    Matthew J LaVoie
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, 77 Avenue Louis Pasteur, HIM 7th Floor, Boston, Massachusetts 02115, USA
    Nat Med 11:1214-21. 2005
    ....
  64. ncbi request reprint Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration
    Dominic M Walsh
    Department of Neurology, Harvard Medical School, Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, MA 02115, USA
    Protein Pept Lett 11:213-28. 2004
    ..With particular reference to AD and PD, we review recent evidence that soluble oligomers are the principal pathogenic species that drive neuronal dysfunction...
  65. ncbi request reprint Physiological regulation of the beta-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiation
    W Taylor Kimberly
    Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
    J Neurosci 25:5533-43. 2005
    ..We conclude that endogenous AICD undergoes tight temporal regulation during the differentiation of neurons and is negatively regulated by JNK3 via phosphorylation of APP at Thr668...
  66. ncbi request reprint Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein
    Wesley Farris
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Biochemistry 44:6513-25. 2005
    ..Our results identify a novel, catalytically inefficient form of IDE expressed in brain and non-neural tissues and recommend novel regions of the IDE gene in which to search for mutations predisposing patients to AD and DM2...
  67. 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
    ....
  68. pmc In vivo cross-linking reveals principally oligomeric forms of α-synuclein and β-synuclein in neurons and non-neural cells
    Ulf Dettmer
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 288:6371-85. 2013
    ..Together with our prior findings, these data suggest that endogenous αSyn exists principally as a 60-kDa tetramer in living cells but is lysis-sensitive, making the study of natural αSyn challenging outside of intact cells...
  69. pmc Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake
    Shaomin Li
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Neuron 62:788-801. 2009
    ..In accord, synaptic glutamate uptake was significantly decreased by soluble Abeta. We conclude that soluble Abeta oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression...
  70. 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
    ....
  71. 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
    ....
  72. doi request reprint Defining the native state of α-synuclein
    Dennis Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, Mass, USA
    Neurodegener Dis 13:114-7. 2014
    ..Thus, αSyn exists natively as helical tetramers that are in dynamic equilibrium with unfolded monomers. The tetramers appear relatively resistant to aggregation, in contrast to monomers, which may give rise to fibrillar inclusions...
  73. pmc A new method for quantitative immunoblotting of endogenous α-synuclein
    Andrew J Newman
    Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
    PLoS ONE 8:e81314. 2013
    ..DSP/β-mercaptoethanol treatment of Western blots should be particularly useful to quantify low-abundance αSyn forms such as extracellular and post-translationally modified αSyn and splice variants...
  74. pmc Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studies
    Nina E Shepardson
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Arch Neurol 68:1239-44. 2011
    ..Therefore, this first part of our review provides the background and rationale for investigating statins as potential therapeutic agents in patients with AD, the subject of the second part...
  75. ncbi request reprint Intraneuronal Abeta42 accumulation in Down syndrome brain
    Chica Mori
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA, USA
    Amyloid 9:88-102. 2002
    ..We conclude that Abeta42 accumulates intracellularly prior to extracellular Abeta deposition in Down syndrome, and that subsequent maturation of extracellular Abeta deposits elicits inflammatory responses andprecedes NFTs...
  76. ncbi request reprint Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide
    Christian Haass
    Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
    Nat Rev Mol Cell Biol 8:101-12. 2007
    ..Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins...
  77. ncbi request reprint Presenilin-1-mediated retention of APP derivatives in early biosynthetic compartments
    Marloes Réchards
    Cell Microscopy Center, Department of Cell Biology, University Medical Center and Institute for Biomembranes, 3584 CX Utrecht, The Netherlands
    Traffic 7:354-64. 2006
    ..Malfunctioning of PS-1 in this role may have important consequences for the progress of AD...
  78. 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...
  79. ncbi request reprint Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo
    Igor Klyubin
    Trinity College Institute of Neuroscience, Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
    Nat Med 11:556-61. 2005
    ....
  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 Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation
    Chianping Ye
    Department of Medicine at Harvard Medical School, Division of Endocrinology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Neurosci Lett 366:320-5. 2004
    ..These findings suggest that PFs may activate neurons differently than fibrils and lend support to the hypothesis that pre-fibrillar assemblies of Abeta may play an important role in the development of AD-type synaptic deficits...
  82. pmc Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization
    Igor Klyubin
    Institute of Neuroscience and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
    J Neurosci 28:4231-7. 2008
    ..Abeta monomer isolated from human CSF did not affect long-term potentiation. These results strongly support a strategy of passive immunization against soluble Abeta oligomers in early Alzheimer's disease...
  83. ncbi request reprint A seed for Alzheimer amyloid in the brain
    Hideki Hayashi
    Department of Dementia Research, National Institute for Longevity Sciences, Obu 474 8522, Japan
    J Neurosci 24:4894-902. 2004
    ..These results imply a mechanism underlying the onset of AD and suggest that an endogenous seed can be a target of therapeutic strategy...
  84. ncbi request reprint The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
    John Hardy
    Laboratories of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA
    Science 297:353-6. 2002
    ..The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance...
  85. ncbi request reprint Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well a
    Qinwen Wang
    Department of Physiology and Pharmacology, Trinity College, Dublin 2, Ireland
    J Neurosci 24:3370-8. 2004
    ..These studies provide evidence that the Abeta-mediated inhibition of LTP induction involves stimulation of the kinases JNK, Cdk5, and p38 MAPK after the activation of both the Abeta receptor(s) and mGluR5...
  86. ncbi request reprint A mathematical model of the impact of novel treatments on the A beta burden in the Alzheimer's brain, CSF and plasma
    David L Craft
    Operations Research Center, MIT, Cambridge, MA 02139, USA
    Bull Math Biol 64:1011-31. 2002
    ..Hence, great care must be taken when interpreting these biomarkers...
  87. ncbi request reprint Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderly
    Wei Qiao Qiu
    Department of Psychiatry, Tufts New England Medical Center, Tufts University School of Medicine, Boston, MA, USA
    Int J Geriatr Psychiatry 22:536-42. 2007
    ..Plasma Amyloid-beta peptide 42 (Abeta42) declines before and soon after the onset of AD, yet the relationship between plasma Abeta42 and depression is unclear...

Research Grants34

  1. Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's Disease
    Dennis Selkoe; Fiscal Year: 2007
    ..New findings emanating from this grant should simultaneously shed light on the physiology of aS and the earliest steps in its pathological oligomerization, with attendant therapeutic insights. ..
  2. Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's Disease
    Dennis Selkoe; Fiscal Year: 2009
    ..New findings emanating from this grant should simultaneously shed light on the physiology of aS and the earliest steps in its pathological oligomerization, with attendant therapeutic insights. ..
  3. Protein-Protein Interactions in the Biology of Beta APP
    Dennis Selkoe; Fiscal Year: 2004
    ..We believe the results could have broad implications for the pathogenesis and treatment of AD as well as for peptide turnover in the brain and the fundamental cell biology of proteases. ..
  4. Protein-Protein Interactions in the Biology of Beta-APP
    Dennis Selkoe; Fiscal Year: 2009
    ..We will also explore new ways to increase the cutting up or the transport of Abeta as future therapeutic approaches for preventing Alzheimer's disease. ..
  5. Protein-Protein Interactions in the Biology of Beta APP
    Dennis Selkoe; Fiscal Year: 2006
    ..We believe the results could have broad implications for the pathogenesis and treatment of AD as well as for peptide turnover in the brain and the fundamental cell biology of proteases. ..
  6. Pathogenic Mechanisms of Cell-Derived Abeta Oligomers
    Dennis Selkoe; Fiscal Year: 2007
    ....
  7. Pathogenic Mechanisms of Cell-Derived Abeta Oligomers
    Dennis Selkoe; Fiscal Year: 2009
    ..abstract_text> ..
  8. Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's Disease
    Dennis J Selkoe; Fiscal Year: 2010
    ..New findings emanating from this grant should simultaneously shed light on the physiology of aS and the earliest steps in its pathological oligomerization, with attendant therapeutic insights. ..
  9. Alpha-Synuclein, PUFA and Membrane Vesicles-Health/PD
    Dennis Selkoe; Fiscal Year: 2006
    ..New findings emanating from this grant should simultaneously shed light on the physiology of aS and the earliest steps in its pathological oligomerization, with attendant therapeutic insights. ..
  10. Protein-Protein Interactions in the Biology of Beta APP
    Dennis Selkoe; Fiscal Year: 2005
    ..We believe the results could have broad implications for the pathogenesis and treatment of AD as well as for peptide turnover in the brain and the fundamental cell biology of proteases. ..
  11. Protein-Protein Interactions in the Biology of Beta APP
    Dennis Selkoe; Fiscal Year: 2003
    ..We believe the results could have broad implications for the pathogenesis and treatment of AD as well as for peptide turnover in the brain and the fundamental cell biology of proteases. ..
  12. PROTEIN/PROTEIN INTERACTIONS IN THE BIOLOGY OF BETA AMYL
    Dennis Selkoe; Fiscal Year: 2001
    ..The results should help open up a new area of AD pathobiology, with attendant therapeutic implications. ..
  13. PROTEIN/PROTEIN INTERACTIONS IN THE BIOLOGY OF BETA AMYL
    Dennis Selkoe; Fiscal Year: 1999
    ..The results should help open up a new area of AD pathobiology, with attendant therapeutic implications. ..
  14. Pathogenic Mechanisms of Cell-Derived Abeta Oligomers
    Dennis J Selkoe; Fiscal Year: 2010
    ..abstract_text> ..
  15. Pathogenic Mechanisms of Cell-Derived Abeta Oligomers
    Dennis Selkoe; Fiscal Year: 2006
    ....
  16. PROTEIN/PROTEIN INTERACTIONS IN THE BIOLOGY OF BETA AMYL
    Dennis Selkoe; Fiscal Year: 2000
    ..The results should help open up a new area of AD pathobiology, with attendant therapeutic implications. ..
  17. Protein-Protein Interactions in the Biology of Beta APP
    Dennis Selkoe; Fiscal Year: 2007
    ..We believe the results could have broad implications for the pathogenesis and treatment of AD as well as for peptide turnover in the brain and the fundamental cell biology of proteases. ..
  18. Aging in the Brain-Role of the Fibrous Proteins
    Dennis Selkoe; Fiscal Year: 2002
    ....
  19. Protein-Protein Interactions in the Biology of Beta-APP
    Dennis J Selkoe; Fiscal Year: 2010
    ..We will also explore new ways to increase the cutting up or the transport of Abeta as future therapeutic approaches for preventing Alzheimer's disease. ..