Research Topics
Species | D M WalshSummaryAffiliation: Harvard University Country: USA Publications
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Publications
The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic interventionD M Walsh
Laboratory for Neurodegenerative Research, Conway Institute, University College Dublin, Republic of Ireland
Biochem Soc Trans 33:1087-90. 2005..In each case, compounds capable of reducing oligomer production or antibodies that avidly bind Abeta oligomers also ameliorate the synaptotoxic effects of these natural, cell-derived oligomers...- 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... - Amyloid-beta oligomers: their production, toxicity and therapeutic inhibitionD M Walsh
Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115, USA
Biochem Soc Trans 30:552-7. 2002.... - A de novo designed helix-turn-helix peptide forms nontoxic amyloid fibrilsY Fezoui
Department of Neurology Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA
Nat Struct Biol 7:1095-9. 2000..These results suggest that the potential to form fibrils under physiologic conditions is not limited to those proteins associated with amyloidoses and that fibril formation alone is not predictive of cytotoxic activity... 
In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692-->Gly) Alzheimer's diseaseD M Walsh
Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston MA 02115, USA
Biochem J 355:869-77. 2001..Increased peptide solubility and assembly stability would favour formation of larger deposits and inhibit their elimination. In addition, increased concentrations of neurotoxic assemblies would accelerate neuronal injury and death...- The APP family of proteins: similarities and differencesD M Walsh
Laboratory for Neurodegenerative Research, Conway Institute, University College Dublin, Republic of Ireland
Biochem Soc Trans 35:416-20. 2007..Here, we will review how knowledge of the similarities and differences between APP and the APLPs may prove useful for the development of novel disease-modifying therapeutics... 
Aberrant protein structure and diseases of the brainA T Welzel
Laboratory for Neurodegenerative Research, Conway Institute of Biomedical and Biomolecular Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland
Ir J Med Sci 180:15-22. 2011..We also discuss possible mechanisms by which aberrant protein structures may mediate disease and the therapeutic opportunities this knowledge offers...- Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradationW Q Qiu
Department of Neurology and Program in Neuroscience, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, Massachusetts 02115 5716, USA
J Biol Chem 273:32730-8. 1998..We conclude that a principal protease capable of down-regulating the levels of secreted Abeta extracellularly is IDE... - 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... - 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... - 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... - 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... - Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseasesG Brent Irvine
School of Medicine and Dentistry, The Queen s University of Belfast, Belfast, Northern Ireland
Mol Med 14:451-64. 2008..In this review, we discuss this theme as it relates to the two most common neurodegenerative conditions-Alzheimer's and Parkinson's diseases... - 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... - 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... - Soluble amyloid-beta peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivoNeng Wei Hu
Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
Brain 131:2414-24. 2008..This strongly indicates that early cognitive deficits can be caused by soluble Abeta independently of deleterious effects on cerebrovascular dynamics... - 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.... - A beta oligomers - a decade of discoveryDominic M Walsh
Laboratory for Neurodegenerative Research, The Conway Institute, University College Dublin, Belfield, Dublin, Republic of Ireland
J Neurochem 101:1172-84. 2007..Here we review recent progress in understanding the role of soluble oligomers in Alzheimer's disease... - 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.... - 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.... - Substrate-targeting gamma-secretase modulatorsThomas L Kukar
Department of Neuroscience, Mayo Clinic, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville, Florida 32224, USA
Nature 453:925-9. 2008..These data also demonstrate the existence and feasibility of 'substrate targeting' by small-molecule effectors of proteolytic enzymes, which if generally applicable may significantly broaden the current notion of 'druggable' targets... - 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... - Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and hostMelanie Meyer-Luehmann
Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, , , Germany
Science 313:1781-4. 2006..The phenotype of the exogenously induced amyloidosis depended on both the host and the source of the agent, suggesting the existence of polymorphic Abeta strains with varying biological activities reminiscent of prion strains... - 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... - Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivoIgor Klyubin
Trinity College Institute of Neuroscience, and Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
Eur J Neurosci 19:2839-46. 2004.... - Soluble oligomers for the diagnosis of neurodegenerative diseasesOmar M A El-Agnaf
Department of Biological Sciences, Lancaster University, Lancaster, UK
Lancet Neurol 2:461-2. 2003 - 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... - Species-specific immune response to immunization with human versus rodent A beta peptideTimothy J Seabrook
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Neurobiol Aging 25:1141-51. 2004..Therefore, immunizing APP-tg and non-tg mice with rodent A beta resulted in a species-specific humoral response with modest T cell reactivity... - Natural oligomers of the amyloid-beta protein specifically disrupt cognitive functionJames P Cleary
Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417, USA
Nat Neurosci 8:79-84. 2005.... - 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... - 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....