Research Topics
Species | D M WalshSummaryAffiliation: University College Dublin Country: Ireland Publications
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Publications
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...- 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... - 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... 
Alzheimer's disease: synaptic dysfunction and AbetaGanesh M Shankar
Center for Neurologic Diseases, Harvard Medical School and Brigham and Women s Hospital, Boston, MA, USA
Mol Neurodegener 4:48. 2009..We also discuss the possible mechanisms of Abeta synaptotoxicity and potential targets for therapeutic intervention...- A facile method for expression and purification of the Alzheimer's disease-associated amyloid beta-peptideDominic M Walsh
Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, Belfield, University College Dublin, Republic of Ireland
FEBS J 276:1266-81. 2009..Recombinant and synthetic peptides exhibited a similar toxic effect on hippocampal neurons, with acute treatment causing inhibition of MTT reduction, and chronic treatment resulting in neuritic degeneration and cell loss... 
gamma-secretase processing of APLP1 leads to the production of a p3-like peptide that does not aggregate and is not toxic to neuronsAedin M Minogue
Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, School of Biomolecular and Biomedical Science, University College Dublin, Belfield, Dublin 4, Republic of Ireland
Brain Res 1262:89-99. 2009..Moreover, using two distinct experimental paradigms, we demonstrate that neither cell-derived nor chemically synthesized ALP-1 influences the oligomerization or aggregation of Abeta...- Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout lifeGanesh M Shankar
Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Sciences, Conway Institute for Biomedical and Biomolecular Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland
Neurobiol Dis 36:293-302. 2009..These data demonstrate the presence of multiple assembly forms of Abeta throughout the life of J20 mice and highlight the difficulty in attributing synaptotoxicity to a single Abeta species... - beta-Secretase cleavage is not required for generation of the intracellular C-terminal domain of the amyloid precursor family of proteinsCarlo Sala Frigerio
Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Republic of Ireland
FEBS J 277:1503-18. 2010..Consequently, whereas inhibition of BACE1 is unlikely to adversely affect potential ICD-mediated signaling, it may alter other important facets of amyloid precursor-like protein/APP biology... - Macroautophagy is not directly involved in the metabolism of amyloid precursor proteinBarry Boland
Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland
J Biol Chem 285:37415-26. 2010..These data suggest that neuronal macroautophagy does not directly regulate APP metabolism but highlights the important anti-amyloidogenic role of lysosomal proteolysis in post-secretase APP-CTF catabolism... - Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysinVicki Betts
Laboratory for Neurodegenerative Research, The Conway Institute for Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland
Neurobiol Dis 31:442-50. 2008..This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation... - Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrilsBRIAN O'NUALLAIN
Laboratory for Neurodegenerative Research, Conway Institute, University College Dublin, Belfield, Dublin 4, Republic of Ireland
J Neurosci 30:14411-9. 2010.... - An NSAID-like compound, FT-9, preferentially inhibits gamma-secretase cleavage of the amyloid precursor protein compared to its effect on amyloid precursor-like protein 1Carlo Sala Frigerio
Laboratory for Neurodegenerative Research, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Republic of Ireland
Biochemistry 48:10894-904. 2009..These findings suggest that selective inhibitors can be developed and that screening of compounds against APP and APLPs should assist in this process... - 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... - Inhibition of amyloid beta protein fibrillation by polymeric nanoparticlesCelia Cabaleiro-Lago
Centre for BioNano Interactions, School of Chemistry and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland
J Am Chem Soc 130:15437-43. 2008..Moreover, we find that fibrillation of Abeta initiated in the absence of nanoparticles can be reversed by addition of nanoparticles up to a particular time point before mature fibrils appear... - 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... - The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementiaJessica M Mc Donald
Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Republic of Ireland
Brain 133:1328-41. 2010..These findings support the hypothesis that soluble amyloid beta-protein is a major correlate of dementia associated with Alzheimer-type pathology and is likely to be intimately involved in the pathogenesis of cognitive failure... - 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... - 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.... - 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... - 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.... - 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... - 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... - 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 - 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.... - 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... - 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... - 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.... - 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.... - 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... - 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... - 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... - 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... - 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... - 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.... - 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... - 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... - 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....