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| Dennis SelkoeSummaryAffiliation: Harvard University Country: USA Publications
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Publications
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivoDominic 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....- Preventing Alzheimer's diseaseDennis 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... 
Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1Tracy 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....- Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylationRichard C Davis
Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523 1870, USA
Mol Neurodegener 6:10. 2011..abstract:.. - Alzheimer's disease: molecular understanding predicts amyloid-based therapeuticsDennis J Selkoe
Harvard Medical School and Brigham and Women s Hospital, Boston, Massachusetts 02115, USA
Annu Rev Pharmacol Toxicol 43:545-84. 2003.... - Folding proteins in fatal waysDennis 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... - Developing preventive therapies for chronic diseases: lessons learned from Alzheimer's diseaseDennis 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... - Notch and Presenilin: regulated intramembrane proteolysis links development and degenerationDennis 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... - Presenilin: running with scissors in the membraneDennis 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... - Deciphering the molecular basis of memory failure in Alzheimer's diseaseDominic 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... - Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendationsNina 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.... - Amyloid beta-peptide is produced by cultured cells during normal metabolism: a repriseDennis 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... - Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memoryGanesh 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... - Altered fatty acid composition of dopaminergic neurons expressing alpha-synuclein and human brains with alpha-synucleinopathiesRonit 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... - A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interferenceTracy 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... - The Notch ligands, Jagged and Delta, are sequentially processed by alpha-secretase and presenilin/gamma-secretase and release signaling fragmentsMatthew 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... - Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavageJay 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.... 
Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer diseaseMatthew 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...- The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's diseaseRonit 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... - gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteinsDominic 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.... - Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimersMatthew 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... - 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 complexPatrick 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... - Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid beta-protein at the cell surfaceJay 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... - Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-proteinWesley 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... - Pink1 Parkinson mutations, the Cdc37/Hsp90 chaperones and Parkin all influence the maturation or subcellular distribution of Pink1Andreas 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... - Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer diseaseMatthew 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... - Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomersMatthew Townsend
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA
Ann Neurol 60:668-76. 2006..INTERPRETATION: A small, orally available natural product penetrates into the brain in vivo to rescue the memory impairment produced by soluble Abeta oligomers through a mechanism that restores hippocampal synaptic plasticity... - Pink1 forms a multiprotein complex with Miro and Milton, linking Pink1 function to mitochondrial traffickingAndreas 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... - 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)... - Toward a remembrance of things past: deciphering Alzheimer diseaseDennis J Selkoe
Department of Neurology, Harvard Medical School, USA
Harvey Lect 99:23-45. 2003 - Purification and characterization of the human gamma-secretase complexPatrick C Fraering
Center for Neurologic Diseases, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
Biochemistry 43:9774-89. 2004.... - Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathwayGanesh 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... - Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substratesAllen 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... - Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivoWesley 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.... - Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathwayMatthew 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.... - A profile of impaired insulin degradation in relation to late-life cognitive decline: a preliminary investigationOlivia 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... 
HLA-DR alleles in amyloid beta-peptide autoimmunity: a highly immunogenic role for the DRB1*1501 alleleVictor 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...- Increased T cell reactivity to amyloid beta protein in older humans and patients with Alzheimer diseaseAlon 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.... - Performance characteristics of plasma amyloid-beta 40 and 42 assaysOlivia 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... - Introducing transglutaminase into the study of Alzheimer's disease. A personal look backDennis 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 - Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathyWesley 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.... - Functional alterations in memory networks in early Alzheimer's diseaseReisa 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... - Amyloid deposition is associated with impaired default network function in older persons without dementiaReisa 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.... - Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behaviorDennis 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... - Biochemical and functional interaction of disrupted-in-schizophrenia 1 and amyloid precursor protein regulates neuronal migration during mammalian cortical developmentTracy 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.... - Ten-year change in plasma amyloid beta levels and late-life cognitive declineOlivia 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... - A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer diseaseWeiming 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.... - Aging, amyloid, and Alzheimer's disease: a perspective in honor of Carl CotmanDennis 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... - Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature deathMalcolm 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... - Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer diseaseDennis 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 - Alzheimer's disease is a synaptic failureDennis 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.... - Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegenerationDominic 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... - Alzheimer's disease abeta vaccine reduces central nervous system abeta levels in a non-human primate, the Caribbean vervetCynthia 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... - Deciphering the genetic basis of Alzheimer's diseaseDennis 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... - Cell biology of protein misfolding: the examples of Alzheimer's and Parkinson's diseasesDennis 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... - Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiationDominic 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.... - Biochemistry. Intramembrane proteases--mixing oil and waterMichael S Wolfe
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA
Science 296:2156-7. 2002 - Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-proteinWesley 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... - Parkin localizes to the Lewy bodies of Parkinson disease and dementia with Lewy bodiesMichael 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... - Physiological regulation of the beta-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiationW 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... - Activity-dependent isolation of the presenilin- gamma -secretase complex reveals nicastrin and a gamma substrateWilliam 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.... - Dopamine covalently modifies and functionally inactivates parkinMatthew 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.... - Proteolysis of chimeric beta-amyloid precursor proteins containing the Notch transmembrane domain yields amyloid beta-like peptidesJimin 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... - Evidence for peripheral clearance of cerebral Abeta protein following chronic, active Abeta immunization in PSAPP miceCynthia 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... - Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptakeShaomin 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... - Complex N-linked glycosylated nicastrin associates with active gamma-secretase and undergoes tight cellular regulationW Taylor Kimberly
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA
J Biol Chem 277:35113-7. 2002.... - Assembly of the gamma-secretase complex involves early formation of an intermediate subcomplex of Aph-1 and nicastrinMatthew 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.... - Cholesterol level and statin use in Alzheimer disease: I. Review of epidemiological and preclinical studiesNina 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... - Presenilin-1-mediated retention of APP derivatives in early biosynthetic compartmentsMarloes 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... - Depression is associated with low plasma Abeta42 independently of cardiovascular disease in the homebound elderlyWei 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... - Amyloid-lowering isocoumarins are not direct inhibitors of gamma-secretaseWilliam P Esler
Nat Cell Biol 4:E110-1; author reply E111-2. 2002 - Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptideChristian 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... - Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivoIgor Klyubin
Trinity College Institute of Neuroscience, Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
Nat Med 11:556-61. 2005.... - Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunizationIgor 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... - The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeuticsJohn 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... - Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activationChianping 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... - A seed for Alzheimer amyloid in the brainHideki 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... - 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 aQinwen 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... - Intraneuronal Abeta42 accumulation in Down syndrome brainChica 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... - A mathematical model of the impact of novel treatments on the A beta burden in the Alzheimer's brain, CSF and plasmaDavid 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... - gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding sitePatrick 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...
Research Grants
- Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's DiseaseDennis 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. ..
- Pathogenic Mechanisms of Cell-Derived Abeta OligomersDennis Selkoe; Fiscal Year: 2007....
- Protein-Protein Interactions in the Biology of Beta APPDennis 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. ..
- Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's DiseaseDennis 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. ..
- Pathogenic Mechanisms of Cell-Derived Abeta OligomersDennis Selkoe; Fiscal Year: 2009..abstract_text> ..
- Protein-Protein Interactions in the Biology of Beta-APPDennis 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. ..
- Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's DiseaseDennis 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. ..
- Pathogenic Mechanisms of Cell-Derived Abeta OligomersDennis J Selkoe; Fiscal Year: 2010..abstract_text> ..
- PROTEIN/PROTEIN INTERACTIONS IN THE BIOLOGY OF BETA AMYLDennis Selkoe; Fiscal Year: 2001..The results should help open up a new area of AD pathobiology, with attendant therapeutic implications. ..
- Aging in the Brain-Role of the Fibrous ProteinsDennis Selkoe; Fiscal Year: 2002....
- Protein-Protein Interactions in the Biology of Beta-APPDennis 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. ..