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Last Name
Institution

Dominic M. Walsh, Ph.D.

TitleAssociate Professor of Neurology
InstitutionBrigham and Women's Hospital
DepartmentNeurology
AddressHarvard Institutes of Medicine
Ctr for Neurologic Disease - HIM 921b
77 Avenue Louis Pasteur
Boston MA 02115
Phone617/525-5059
Fax617/525-5252

 Mentoring 
 current student opportunities
Available: 09/30/13, Expires: 09/30/14

Compelling genetic evidence links the principal component of amyloid plaques, the amyloid beta-protein (Abeta), to Alzheimer’s disease (AD). However, clinical trials of Abeta-targeting agents have proved disappointing and there is lingering concern about the relevance of Abeta to AD causation. Unlike agents in other conditions, there is no robust connection between fibrillar Abeta pathology and disease, i.e. plaque density and number poorly correlate with the presence and severity of disease. An explanation for this apparent lack of pathological cause and effect is that histologically invisible soluble forms of Abeta, loosely referred to as “oligomers”, are the primary mediators of neurotoxicity. While numerous studies indicate that oligomers formed in vitro have toxic activity, surprisingly little effort has been devoted to analyzing bioactive forms of brain-derived Abeta. Research by the PI has demonstrated that water-soluble Abeta (WS-Abeta) extracted from AD brain can alter synaptic structure and function when applied to cultured neurons or injected into the brains of rodents. The objective of this project is to determine whether toxic brain Abeta species really do cause AD. Put simply, if Abeta is the initiator of a pathogenic cascade that causes AD, then it follows that a person cannot develop AD without being exposed to significant levels of WS-Abeta. Similarly, an individual would rarely have appreciable amounts of WS-Abeta without having the disease. Hence a test of the causal role of Abeta can be approached in a single large-scale experiment, i.e. to measure the levels of WS-Abeta in the brains of individuals who died in early/moderate stage AD vs. those who died free of AD. If WS-Abeta causes AD, we should detect abundant bioactive material in the AD brain but little or none in the brains of cognitively normal humans.
While the principle of this approach is straightforward, the practicalities are potentially challenging. First, how do we overcome the confounding possibility that the non-demented group may be “contaminated” by cases of incipient AD? Second, how do we control for material artefactually released from plaques? In regard to the first question, recent longitudinal studies on patients with mild cognitive impairment and individuals with dominantly inherited forms of AD indicate that CSF biomarkers can accurately predict onset of AD 5-10 years in advance. Thus we plan to measure CSF biomarkers to confirm the authenticity of our diseased and disease-free samples and then test if the levels of WS-Abeta really segregate with disease. The second issue can be controlled for by utilizing tissue from non-demented, biomarker-negative individuals that have abundant amyloid pathology.
In this project we will also classify and document the types of amyloid deposits so as to understand if there is a link between the presence of certain types of amyloid deposits, WS-Abeta and the presence of AD-type dementia. Understanding this link should hasten the development of better disease biomarkers and facilitate the development of novel therapeutics designed to target water-soluble Abeta. As part of this effort the MD student will prepare and analyze homogenates from the brains of non-demented controls and individuals who died of AD. Analysis will involve the use of a variety of standard biochemical and immunological techniques including: ELISA, sedimentation analysis, size exclusion chromatography, immunoprecipitation and Western blotting. The student will have the opportunity to work as part of a team which will include a postdoctoral protein biochemist, a neuropathologist and the PI.

Available: 09/03/12, Expires: 06/30/16

The subtlety and variability of the earliest amnestic symptoms of Alzheimer disease (AD) indicate that something is discretely and intermittently interrupting the function of synapses that encode new declarative memories. A wealth of findings now suggests that this “something” is the amyloid beta-protein (Abeta), a hydrophobic peptide with an ominous tendency to assemble into long-lived oligomers and polymers. Research by the PI has demonstrated that water-soluble Abeta extracted from AD brain can alter synaptic structure and function when applied to cultured neurons or injected into the brains of rodents. However, linking water-soluble Abeta and insoluble amyloid plaques (a pathological hallmark of AD) with the presence and severity of AD-type dementia is complicated by the fact that certain cognitively intact cases have appreciable amyloid pathology and relatively high levels of water-soluble Abeta. Although it is tempting to speculate that these individuals would in time develop AD, we simply do not know. Thus in this project we will acquire antemortem biomarker information to facilitate the study of 2 distinct categories of cognitively normal individuals: those with little risk of developing AD and those likely to develop AD. Similarly, we will also better characterize the amyloid deposits in the brain regions used for biochemical analysis. For instance, it has been reported that differences in plaque morphology are evident between demented cases and non-demented cases and that dementia can develop in the absence of significant plaque pathology.

In this project we will classify and document the types of amyloid deposits so as to understand if there is a link between the presence of certain types of amyloid deposits, water-soluble Abeta and the presence of AD-type dementia. Understanding this link should hasten the development of better disease biomarkers and facilitate the development of novel therapeutics designed to target water-soluble Abeta. As part of this effort the MD student will prepare and analyze homogenates from the brains of non-demented controls and individuals who died of AD. Analysis will involve the use of a variety of standard biochemical and immunological techniques including: ELISA, sedimentation analysis, size exclusion chromatography, immunoprecipitation and Western blotting. The student will have the opportunity to work as part of a team which will include a postdoctoral protein biochemist, a neuropathologist and the PI.


 Bibliographic 
 selected publications
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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  1. Klyubin I, Ondrejcak T, Hayes J, Cullen WK, Mably AJ, Walsh DM, Rowan MJ. Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aß in vivo. Philos Trans R Soc Lond B Biol Sci. 2014; 369(1633):20130147.
    View in: PubMed
  2. An K, Klyubin I, Kim Y, Jung JH, Mably AJ, O'Dowd ST, Lynch T, Kanmert D, Lemere CA, Finan GM, Park JW, Kim TW, Walsh DM, Rowan MJ, Kim JH. Exosomes neutralize synaptic-plasticity-disrupting activity of Aß assemblies in vivo. Mol Brain. 2013; 6(1):47.
    View in: PubMed
  3. Nicoll AJ, Panico S, Freir DB, Wright D, Terry C, Risse E, Herron CE, O'Malley T, Wadsworth JD, Farrow MA, Walsh DM, Saibil HR, Collinge J. Amyloid-ß nanotubes are associated with prion protein-dependent synaptotoxicity. Nat Commun. 2013 Sep 11; 4:2416.
    View in: PubMed
  4. Wong HK, Veremeyko T, Patel N, Lemere CA, Walsh DM, Esau C, Vanderburg C, Krichevsky AM. De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease. Hum Mol Genet. 2013 Aug 1; 22(15):3077-92.
    View in: PubMed
  5. Yang T, Hong S, O'Malley T, Sperling RA, Walsh DM, Selkoe DJ. New ELISAs with high specificity for soluble oligomers of amyloid ß-protein detect natural Aß oligomers in human brain but not CSF. Alzheimers Dement. 2013 Mar; 9(2):99-112.
    View in: PubMed
  6. O'Dowd ST, Ardah MT, Johansson P, Lomakin A, Benedek GB, Roberts KA, Cummins G, El Agnaf OM, Svensson J, Zetterberg H, Lynch T, Walsh DM. The ELISA-Measured Increase in Cerebrospinal Fluid Tau that Discriminates Alzheimer's Disease from other Neurodegenerative Disorders is not Attributable to Differential Recognition of Tau Assembly Forms. J Alzheimers Dis. 2013 Jan 1; 33(4):923-8.
    View in: PubMed
  7. Welzel AT, Williams AD, McWilliams-Koeppen HP, Acero L, Weber A, Blinder V, Mably A, Bunk S, Hermann C, Farrell MA, Ehrlich HJ, Schwarz HP, Walsh DM, Solomon A, O'Nuallain B. Human Anti-Aß IgGs Target Conformational Epitopes on Synthetic Dimer Assemblies and the AD Brain-Derived Peptide. PLoS One. 2012; 7(11):e50317.
    View in: PubMed
  8. Borlikova GG, Trejo M, Mably AJ, Mc Donald JM, Sala Frigerio C, Regan CM, Murphy KJ, Masliah E, Walsh DM. Alzheimer brain-derived amyloid ß-protein impairs synaptic remodeling and memory consolidation. Neurobiol Aging. 2013 May; 34(5):1315-27.
    View in: PubMed
  9. Moro ML, Giaccone G, Lombardi R, Indaco A, Uggetti A, Morbin M, Saccucci S, Di Fede G, Catania M, Walsh DM, Demarchi A, Rozemuller A, Bogdanovic N, Bugiani O, Ghetti B, Tagliavini F. APP mutations in the Aß coding region are associated with abundant cerebral deposition of Aß38. Acta Neuropathol. 2012 Dec; 124(6):809-21.
    View in: PubMed
  10. Cukalevski R, Boland B, Frohm B, Thulin E, Walsh D, Linse S. Role of Aromatic Side Chains in Amyloid ß-Protein Aggregation. ACS Chem Neurosci. 2012 Dec 19; 3(12):1008-16.
    View in: PubMed
  11. Nicholson AM, Wold LA, Walsh DM, Ferreira A. ß-Amyloid carrying the Dutch mutation has diverse effects on calpain-mediated toxicity in hippocampal neurons. Mol Med. 2012; 18:178-85.
    View in: PubMed
  12. McDonald JM, Cairns NJ, Taylor-Reinwald L, Holtzman D, Walsh DM. The levels of water-soluble and triton-soluble Aß are increased in Alzheimer's disease brain. Brain Res. 2012 Apr 23; 1450:138-47.
    View in: PubMed
  13. Walsh DM, Teplow DB. Alzheimer's Disease and the Amyloid ß-Protein. Prog Mol Biol Transl Sci. 2012; 107:101-24.
    View in: PubMed
  14. Bieschke J, Herbst M, Wiglenda T, Friedrich RP, Boeddrich A, Schiele F, Kleckers D, Lopez del Amo JM, Grüning BA, Wang Q, Schmidt MR, Lurz R, Anwyl R, Schnoegl S, Fändrich M, Frank RF, Reif B, Günther S, Walsh DM, Wanker EE. Small-molecule conversion of toxic oligomers to nontoxic ß-sheet-rich amyloid fibrils. Nat Chem Biol. 2012 Jan; 8(1):93-101.
    View in: PubMed
  15. O'Nuallain B, Klyubin I, Mc Donald JM, Foster JS, Welzel A, Barry A, Dykoski RK, Cleary JP, Gebbink MF, Rowan MJ, Walsh DM. A monoclonal antibody against synthetic Aß dimer assemblies neutralizes brain-derived synaptic plasticity-disrupting Aß. J Neurochem. 2011 Oct; 119(1):189-201.
    View in: PubMed
  16. Freir DB, Nicoll AJ, Klyubin I, Panico S, Mc Donald JM, Risse E, Asante EA, Farrow MA, Sessions RB, Saibil HR, Clarke AR, Rowan MJ, Walsh DM, Collinge J. Interaction between prion protein and toxic amyloid ß assemblies can be therapeutically targeted at multiple sites. Nat Commun. 2011; 2:336.
    View in: PubMed
  17. Barry AE, Klyubin I, Mc Donald JM, Mably AJ, Farrell MA, Scott M, Walsh DM, Rowan MJ. Alzheimer's disease brain-derived amyloid-ß-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci. 2011 May 18; 31(20):7259-63.
    View in: PubMed
  18. Kumar S, Rezaei-Ghaleh N, Terwel D, Thal DR, Richard M, Hoch M, Mc Donald JM, Wüllner U, Glebov K, Heneka MT, Walsh DM, Zweckstetter M, Walter J. Extracellular phosphorylation of the amyloid ß-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. EMBO J. 2011 Jun 1; 30(11):2255-65.
    View in: PubMed
  19. Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ. Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A. 2011 Apr 5; 108(14):5819-24.
    View in: PubMed
  20. Shankar GM, Welzel AT, McDonald JM, Selkoe DJ, Walsh DM. Isolation of low-n amyloid ß-protein oligomers from cultured cells, CSF, and brain. Methods Mol Biol. 2011; 670:33-44.
    View in: PubMed
  21. O'Nuallain B, Freir DB, Nicoll AJ, Risse E, Ferguson N, Herron CE, Collinge J, Walsh DM. Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils. J Neurosci. 2010 Oct 27; 30(43):14411-9.
    View in: PubMed
  22. Welzel AT, Walsh DM. Aberrant protein structure and diseases of the brain. Ir J Med Sci. 2011 Mar; 180(1):15-22.
    View in: PubMed
  23. Boland B, Smith DA, Mooney D, Jung SS, Walsh DM, Platt FM. Macroautophagy is not directly involved in the metabolism of amyloid precursor protein. J Biol Chem. 2010 Nov 26; 285(48):37415-26.
    View in: PubMed
  24. Mc Donald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, Selkoe DJ, Ince PG, Walsh DM. The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain. 2010 May; 133(Pt 5):1328-41.
    View in: PubMed
  25. Sala Frigerio C, Fadeeva JV, Minogue AM, Citron M, Van Leuven F, Staufenbiel M, Paganetti P, Selkoe DJ, Walsh DM. beta-Secretase cleavage is not required for generation of the intracellular C-terminal domain of the amyloid precursor family of proteins. FEBS J. 2010 Mar; 277(6):1503-18.
    View in: PubMed
  26. Freir DB, Fedriani R, Scully D, Smith IM, Selkoe DJ, Walsh DM, Regan CM. Aß oligomers inhibit synapse remodelling necessary for memory consolidation. Neurobiol Aging. 2011 Dec; 32(12):2211-8.
    View in: PubMed
  27. Reed MN, Hofmeister JJ, Jungbauer L, Welzel AT, Yu C, Sherman MA, Lesné S, LaDu MJ, Walsh DM, Ashe KH, Cleary JP. Cognitive effects of cell-derived and synthetically derived Aß oligomers. Neurobiol Aging. 2011 Oct; 32(10):1784-94.
    View in: PubMed
  28. Sala Frigerio C, Kukar TL, Fauq A, Engel PC, Golde TE, Walsh DM. 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 1. Biochemistry. 2009 Nov 24; 48(46):10894-904.
    View in: PubMed
  29. Shankar GM, Walsh DM. Alzheimer's disease: synaptic dysfunction and Abeta. Mol Neurodegener. 2009; 4:48.
    View in: PubMed
  30. Hellstrand E, Boland B, Walsh DM, Linse S. Amyloid ß-Protein Aggregation Produces Highly Reproducible Kinetic Data and Occurs by a Two-Phase Process. ACS Chem Neurosci. 2010 Jan 20; 1(1):13-8.
    View in: PubMed
  31. Hampel H, Shen Y, Walsh DM, Aisen P, Shaw LM, Zetterberg H, Trojanowski JQ, Blennow K. Biological markers of amyloid beta-related mechanisms in Alzheimer's disease. Exp Neurol. 2010 Jun; 223(2):334-46.
    View in: PubMed
  32. Shankar GM, Leissring MA, Adame A, Sun X, Spooner E, Masliah E, Selkoe DJ, Lemere CA, Walsh DM. Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life. Neurobiol Dis. 2009 Nov; 36(2):293-302.
    View in: PubMed
  33. Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25; 62(6):788-801.
    View in: PubMed
  34. Walsh DM, Thulin E, Minogue AM, Gustavsson N, Pang E, Teplow DB, Linse S. A facile method for expression and purification of the Alzheimer's disease-associated amyloid beta-peptide. FEBS J. 2009 Mar; 276(5):1266-81.
    View in: PubMed
  35. Xia W, Yang T, Shankar G, Smith IM, Shen Y, Walsh DM, Selkoe DJ. A specific enzyme-linked immunosorbent assay for measuring beta-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Arch Neurol. 2009 Feb; 66(2):190-9.
    View in: PubMed
  36. Minogue AM, Stubbs AK, Frigerio CS, Boland B, Fadeeva JV, Tang J, Selkoe DJ, Walsh DM. gamma-secretase processing of APLP1 leads to the production of a p3-like peptide that does not aggregate and is not toxic to neurons. Brain Res. 2009 Mar 25; 1262:89-99.
    View in: PubMed
  37. Cabaleiro-Lago C, Quinlan-Pluck F, Lynch I, Lindman S, Minogue AM, Thulin E, Walsh DM, Dawson KA, Linse S. Inhibition of amyloid beta protein fibrillation by polymeric nanoparticles. J Am Chem Soc. 2008 Nov 19; 130(46):15437-43.
    View in: PubMed
  38. Hu NW, Smith IM, Walsh DM, Rowan MJ. Soluble amyloid-beta peptides potently disrupt hippocampal synaptic plasticity in the absence of cerebrovascular dysfunction in vivo. Brain. 2008 Sep; 131(Pt 9):2414-24.
    View in: PubMed
  39. Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM. Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases. Mol Med. 2008 Jul-Aug; 14(7-8):451-64.
    View in: PubMed
  40. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008 Aug; 14(8):837-42.
    View in: PubMed
  41. Betts V, Leissring MA, Dolios G, Wang R, Selkoe DJ, Walsh DM. Aggregation and catabolism of disease-associated intra-Abeta mutations: reduced proteolysis of AbetaA21G by neprilysin. Neurobiol Dis. 2008 Sep; 31(3):442-50.
    View in: PubMed
  42. Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price RW, Moore B, Rangachari V, Cusack B, Eriksen J, Jansen-West K, Verbeeck C, Yager D, Eckman C, Ye W, Sagi S, Cottrell BA, Torpey J, Rosenberry TL, Fauq A, Wolfe MS, Schmidt B, Walsh DM, Koo EH, Golde TE. Substrate-targeting gamma-secretase modulators. Nature. 2008 Jun 12; 453(7197):925-9.
    View in: PubMed
  43. Klyubin I, Betts V, Welzel AT, Blennow K, Zetterberg H, Wallin A, Lemere CA, Cullen WK, Peng Y, Wisniewski T, Selkoe DJ, Anwyl R, Walsh DM, Rowan MJ. Amyloid beta protein dimer-containing human CSF disrupts synaptic plasticity: prevention by systemic passive immunization. J Neurosci. 2008 Apr 16; 28(16):4231-7.
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  44. McDonough SM, Liddle SD, Hunter R, Walsh DM, Glasgow P, Gormley G, Hurley D, Delitto A, Park J, Bradbury I, Baxter GD. Exercise and manual auricular acupuncture: a pilot assessor-blind randomised controlled trial. (The acupuncture and personalised exercise programme (APEP) trial). BMC Musculoskelet Disord. 2008; 9:31.
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  45. Farris W, Schütz SG, Cirrito JR, Shankar GM, Sun X, George A, Leissring MA, Walsh DM, Qiu WQ, Holtzman DM, Selkoe DJ. Loss of neprilysin function promotes amyloid plaque formation and causes cerebral amyloid angiopathy. Am J Pathol. 2007 Jul; 171(1):241-51.
    View in: PubMed
  46. Walsh DM, Minogue AM, Sala Frigerio C, Fadeeva JV, Wasco W, Selkoe DJ. The APP family of proteins: similarities and differences. Biochem Soc Trans. 2007 Apr; 35(Pt 2):416-20.
    View in: PubMed
  47. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci. 2007 Mar 14; 27(11):2866-75.
    View in: PubMed
  48. Walsh DM, Selkoe DJ. A beta oligomers - a decade of discovery. J Neurochem. 2007 Jun; 101(5):1172-84.
    View in: PubMed
  49. Walsh DM, Finwall J, Touchette PE, McGregor MR, Fernandez GE, Lott IT, Sandman CA. Rapid assessment of severe cognitive impairment in individuals with developmental disabilities. J Intellect Disabil Res. 2007 Feb; 51(Pt 2):91-100.
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  50. Townsend M, Cleary JP, Mehta T, Hofmeister J, Lesne S, O'Hare E, Walsh DM, Selkoe DJ. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-beta oligomers. Ann Neurol. 2006 Dec; 60(6):668-76.
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  51. Beal MF, Bossy-Wetzel E, Finkbeiner S, Fiskum G, Giasson B, Johnson C, Khachaturian ZS, Lee VM, Nicholls D, Reddy H, Reynolds I, Teplow DB, Thal LJ, Trojanowski JQ, Walsh DM, Wetzel R, Wexler NS, Young AB, Bain L. Common threads in neurodegenerative disorders of aging. Alzheimers Dement. 2006 Oct; 2(4):322-6.
    View in: PubMed
  52. Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22; 313(5794):1781-4.
    View in: PubMed
  53. Townsend M, Shankar GM, Mehta T, Walsh DM, Selkoe DJ. Effects of secreted oligomers of amyloid beta-protein on hippocampal synaptic plasticity: a potent role for trimers. J Physiol. 2006 Apr 15; 572(Pt 2):477-92.
    View in: PubMed
  54. Walsh DM, Klyubin I, Shankar GM, Townsend M, Fadeeva JV, Betts V, Podlisny MB, Cleary JP, Ashe KH, Rowan MJ, Selkoe DJ. The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention. Biochem Soc Trans. 2005 Nov; 33(Pt 5):1087-90.
    View in: PubMed
  55. Klyubin I, Walsh DM, Lemere CA, Cullen WK, Shankar GM, Betts V, Spooner ET, Jiang L, Anwyl R, Selkoe DJ, Rowan MJ. Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo. Nat Med. 2005 May; 11(5):556-61.
    View in: PubMed
  56. Walsh DM, Townsend M, Podlisny MB, Shankar GM, Fadeeva JV, El Agnaf O, Hartley DM, Selkoe DJ. Certain inhibitors of synthetic amyloid beta-peptide (Abeta) fibrillogenesis block oligomerization of natural Abeta and thereby rescue long-term potentiation. J Neurosci. 2005 Mar 9; 25(10):2455-62.
    View in: PubMed
  57. Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat Neurosci. 2005 Jan; 8(1):79-84.
    View in: PubMed
  58. Seabrook TJ, Bloom JK, Iglesias M, Spooner ET, Walsh DM, Lemere CA. Species-specific immune response to immunization with human versus rodent A beta peptide. Neurobiol Aging. 2004 Oct; 25(9):1141-51.
    View in: PubMed
  59. Walsh DM, Selkoe DJ. Deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron. 2004 Sep 30; 44(1):181-93.
    View in: PubMed
  60. Ye C, Walsh DM, Selkoe DJ, Hartley DM. Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation. Neurosci Lett. 2004 Aug 19; 366(3):320-5.
    View in: PubMed
  61. Walsh DM, Selkoe DJ. Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept Lett. 2004 Jun; 11(3):213-28.
    View in: PubMed
  62. Klyubin I, Walsh DM, Cullen WK, Fadeeva JV, Anwyl R, Selkoe DJ, Rowan MJ. Soluble Arctic amyloid beta protein inhibits hippocampal long-term potentiation in vivo. Eur J Neurosci. 2004 May; 19(10):2839-46.
    View in: PubMed
  63. Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. 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 as metabotropic glutamate receptor type 5. J Neurosci. 2004 Mar 31; 24(13):3370-8.
    View in: PubMed
  64. Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X, Frosch MP, Selkoe DJ. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron. 2003 Dec 18; 40(6):1087-93.
    View in: PubMed
  65. El-Agnaf OM, Walsh DM, Allsop D. Soluble oligomers for the diagnosis of neurodegenerative diseases. Lancet Neurol. 2003 Aug; 2(8):461-2.
    View in: PubMed
  66. Walsh DM, Fadeeva JV, LaVoie MJ, Paliga K, Eggert S, Kimberly WT, Wasco W, Selkoe DJ. gamma-Secretase cleavage and binding to FE65 regulate the nuclear translocation of the intracellular C-terminal domain (ICD) of the APP family of proteins. Biochemistry. 2003 Jun 10; 42(22):6664-73.
    View in: PubMed
  67. Kimberly WT, Kovacs DM, Walsh D, Lashuel H, Lemere CA. The 8th International Conference on Alzheimer's Disease and Related Disorders, July 20-25, 2002, Stockholm, Sweden. Amyloid. 2003 Mar; 10(1):51-61.
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  68. Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron. 2003 Feb 20; 37(4):583-95.
    View in: PubMed
  69. Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ. Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem Soc Trans. 2002 Aug; 30(4):552-7.
    View in: PubMed
  70. Walsh DM, Klyubin I, Fadeeva JV, Cullen WK, Anwyl R, Wolfe MS, Rowan MJ, Selkoe DJ. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature. 2002 Apr 4; 416(6880):535-9.
    View in: PubMed
  71. Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB. In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692-->Gly) Alzheimer's disease. Biochem J. 2001 May 1; 355(Pt 3):869-77.
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  72. Fezoui Y, Hartley DM, Walsh DM, Selkoe DJ, Osterhout JJ, Teplow DB. A de novo designed helix-turn-helix peptide forms nontoxic amyloid fibrils. Nat Struct Biol. 2000 Dec; 7(12):1095-9.
    View in: PubMed
  73. Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ. The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry. 2000 Sep 5; 39(35):10831-9.
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  74. Fezoui Y, Hartley DM, Harper JD, Khurana R, Walsh DM, Condron MM, Selkoe DJ, Lansbury PT, Fink AL, Teplow DB. An improved method of preparing the amyloid beta-protein for fibrillogenesis and neurotoxicity experiments. Amyloid. 2000 Sep; 7(3):166-78.
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  75. Barlas P, Craig JA, Robinson J, Walsh DM, Baxter GD, Allen JM. Managing delayed-onset muscle soreness: lack of effect of selected oral systemic analgesics. Arch Phys Med Rehabil. 2000 Jul; 81(7):966-72.
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  76. Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ. Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999 Oct 15; 19(20):8876-84.
    View in: PubMed
  77. Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem. 1999 Sep 3; 274(36):25945-52.
    View in: PubMed
  78. Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem. 1998 Dec 4; 273(49):32730-8.
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  79. El-Agnaf OM, Guthrie DJ, Walsh DM, Irvine GB. The influence of the central region containing residues 19-25 on the aggregation properties and secondary structure of Alzheimer's beta-amyloid peptide. Eur J Biochem. 1998 Sep 15; 256(3):560-9.
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  80. Podlisny MB, Walsh DM, Amarante P, Ostaszewski BL, Stimson ER, Maggio JE, Teplow DB, Selkoe DJ. Oligomerization of endogenous and synthetic amyloid beta-protein at nanomolar levels in cell culture and stabilization of monomer by Congo red. Biochemistry. 1998 Mar 17; 37(11):3602-11.
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  81. Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB. Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem. 1997 Aug 29; 272(35):22364-72.
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  82. Clements A, Allsop D, Walsh DM, Williams CH. Aggregation and metal-binding properties of mutant forms of the amyloid A beta peptide of Alzheimer's disease. J Neurochem. 1996 Feb; 66(2):740-7.
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  83. el-Agnaf OM, Irvine GB, Guthrie DJ, Walsh DM. Properties of some peptides related to amyloid beta-peptide. Biochem Soc Trans. 1996 Feb; 24(1):59S.
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  84. Stables JM, Beresford IJ, Arkinstall S, Ireland SJ, Walsh DM, Seale PW, Ward P, Hagan RM. GR138676, a novel peptidic tachykinin antagonist which is potent at NK3 receptors. Neuropeptides. 1994 Dec; 27(6):333-41.
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  85. Walsh DM, Williams CH, Kennedy HE, Allsop D. An investigation into the proteolytic cleavage of Alzheimer amyloid precursor protein in PC-12 cells. Biochem Soc Trans. 1994 Feb; 22(1):14S.
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  86. Clements A, Walsh DM, Williams CH, Allsop D. Aggregation of Alzheimer's peptides. Biochem Soc Trans. 1994 Feb; 22(1):16S.
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  87. Walsh DM, Williams CH, Kennedy HE, Allsop D, Murphy G. Gelatinase A not alpha-secretase? Nature. 1994 Jan 6; 367(6458):27-8.
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  88. Clements A, Walsh DM, Williams CH, Allsop D. Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid beta/A4 peptide. Neurosci Lett. 1993 Oct 14; 161(1):17-20.
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  89. Williams CH, Yamamoto T, Walsh DM, Allsop D. Endopeptidase 3.4.24.11 converts N-1-(R,S)carboxy-3-phenylpropyl-Ala-Ala-Phe-p-carboxyanilide into a potent inhibitor of angiotensin-converting enzyme. Biochem J. 1993 Sep 15; 294 ( Pt 3):681-4.
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  90. Elliott PJ, Walsh DM, Close SP. Dopamine D1 and D2 receptor interactions in the MPTP-treated marmoset. Neurosci Lett. 1992 Aug 3; 142(1):1-4.
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  91. Walsh DM, Kennedy S, Blanchflower WJ, Kennedy DG. The effect of vitamin E and/or selenium depletion on tissue peroxidation and peroxidisability in ruminant cattle. Biochem Soc Trans. 1991 Feb; 19(1):61S.
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