Bradley Hyman

Summary

Affiliation: Massachusetts General Hospital
Country: USA

Publications

  1. ncbi request reprint Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme
    Robert Spoelgen
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 26:418-28. 2006
  2. pmc Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain
    Phillip B Jones
    Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
    PLoS ONE 6:e14586. 2011
  3. pmc In vivo imaging of alpha-synuclein in mouse cortex demonstrates stable expression and differential subcellular compartment mobility
    Vivek K Unni
    Alzheimer s Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH Harvard Medical School, Charlestown, Massachusetts, United States of America
    PLoS ONE 5:e10589. 2010
  4. pmc Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease
    Shuko Takeda
    Alzheimer s Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 16th St, Charlestown, MA 02129, USA
    FASEB J 27:3239-48. 2013
  5. doi request reprint Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology
    Bradley T Hyman
    Neurology Service, Massachusetts General Hospital, 114 16th Street Charlestown, Massachusetts 01029, USA
    Nat Rev Neurosci 13:395-406. 2012
  6. pmc Alzheimer's disease: synapses gone cold
    Robert M Koffie
    Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA
    Mol Neurodegener 6:63. 2011
  7. pmc Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575
    Monica Garcia-Alloza
    MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Mol Neurodegener 4:19. 2009
  8. pmc T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice
    Melanie Meyer-Luehmann
    MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Alzheimer s Disease Research Laboratory, 02129 Charlestown, MA USA
    Mol Neurodegener 6:22. 2011
  9. ncbi request reprint Transcriptional and conformational changes of the tau molecule in Alzheimer's disease
    Bradley T Hyman
    Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Biochim Biophys Acta 1739:150-7. 2005
  10. ncbi request reprint The intracellular domain of the low density lipoprotein receptor-related protein modulates transactivation mediated by amyloid precursor protein and Fe65
    Ayae Kinoshita
    Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Biol Chem 278:41182-8. 2003

Research Grants

  1. Neurologic Alterations in Alzheimer's Disease
    Bradley T Hyman; Fiscal Year: 2010
  2. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2006
  3. LRP AND ALZHEIMER'S DISEASE
    Bradley Hyman; Fiscal Year: 2007
  4. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2007
  5. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2009
  6. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2009
  7. Anatomical Changes in Tau Transgenic Models
    Bradley T Hyman; Fiscal Year: 2010
  8. NEUROPATHOLOGICAL ALTERATIONS IN ALZHEIMERS DISEASE
    Bradley Hyman; Fiscal Year: 1999
  9. NEUROPATHOLOGICAL ALTERATIONS IN ALZHEIMERS DISEASE
    Bradley Hyman; Fiscal Year: 1999
  10. Anatomical changes in tau trangenic models
    Bradley T Hyman; Fiscal Year: 2010

Collaborators

Detail Information

Publications88

  1. ncbi request reprint Interaction of the cytosolic domains of sorLA/LR11 with the amyloid precursor protein (APP) and beta-secretase beta-site APP-cleaving enzyme
    Robert Spoelgen
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 26:418-28. 2006
    ..We discovered that sorLA significantly reduced BACE-APP interactions in Golgi. We postulate that sorLA acts as a trafficking receptor that prevents BACE-APP interactions and hence BACE cleavage of APP...
  2. pmc Apolipoprotein E: isoform specific differences in tertiary structure and interaction with amyloid-β in human Alzheimer brain
    Phillip B Jones
    Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
    PLoS ONE 6:e14586. 2011
    ....
  3. pmc In vivo imaging of alpha-synuclein in mouse cortex demonstrates stable expression and differential subcellular compartment mobility
    Vivek K Unni
    Alzheimer s Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH Harvard Medical School, Charlestown, Massachusetts, United States of America
    PLoS ONE 5:e10589. 2010
    ..We now develop methods to measure alpha-synuclein levels in the living mammalian brain to study in vivo protein mobility, turnover and degradation with subcellular specificity...
  4. pmc Brain interstitial oligomeric amyloid β increases with age and is resistant to clearance from brain in a mouse model of Alzheimer's disease
    Shuko Takeda
    Alzheimer s Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, 16th St, Charlestown, MA 02129, USA
    FASEB J 27:3239-48. 2013
    ..01)], suggesting that HMW Aβ oligomers clear more slowly than other forms from the brain. These data reveal the dynamic metabolism of neurotoxic Aβ oligomers in AD brain and could provide new insights into Aβ-targeted therapies for AD...
  5. doi request reprint Apoptotic and non-apoptotic roles of caspases in neuronal physiology and pathophysiology
    Bradley T Hyman
    Neurology Service, Massachusetts General Hospital, 114 16th Street Charlestown, Massachusetts 01029, USA
    Nat Rev Neurosci 13:395-406. 2012
    ..This Review explores the multiple roles of caspase activity in neurons...
  6. pmc Alzheimer's disease: synapses gone cold
    Robert M Koffie
    Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA
    Mol Neurodegener 6:63. 2011
    ..Here, we review recent findings concerning AD pathogenesis with a particular focus on how Aβ impacts synapses...
  7. pmc Existing plaques and neuritic abnormalities in APP:PS1 mice are not affected by administration of the gamma-secretase inhibitor LY-411575
    Monica Garcia-Alloza
    MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Mol Neurodegener 4:19. 2009
    ..Therefore, a combination therapy of Abeta suppression with agents that increase clearance of amyloid and/or prevent neurotoxicity might be needed for a more effective treatment in patients with pre-existing pathology...
  8. pmc T cell mediated cerebral hemorrhages and microhemorrhages during passive Aβ immunization in APPPS1 transgenic mice
    Melanie Meyer-Luehmann
    MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Alzheimer s Disease Research Laboratory, 02129 Charlestown, MA USA
    Mol Neurodegener 6:22. 2011
    ..Neuropathological investigations of patients who died after the trial showed clearance of amyloid pathology, but also a powerful immune response involving activated T cells probably underlying the negative effects of the immunization...
  9. ncbi request reprint Transcriptional and conformational changes of the tau molecule in Alzheimer's disease
    Bradley T Hyman
    Department of Neurology, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Biochim Biophys Acta 1739:150-7. 2005
    ....
  10. ncbi request reprint The intracellular domain of the low density lipoprotein receptor-related protein modulates transactivation mediated by amyloid precursor protein and Fe65
    Ayae Kinoshita
    Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Biol Chem 278:41182-8. 2003
    ....
  11. ncbi request reprint Nonsteroidal anti-inflammatory drugs lower Abeta42 and change presenilin 1 conformation
    Alberto Lleo
    Alzheimer Research Unit, Massachusetts General Hospital, 114 16th St, Charlestown, Massachusetts 02129, USA
    Nat Med 10:1065-6. 2004
    ....
  12. ncbi request reprint Notch1 competes with the amyloid precursor protein for gamma-secretase and down-regulates presenilin-1 gene expression
    Alberto Lleo
    Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02114, USA
    J Biol Chem 278:47370-5. 2003
    ..This finding suggests that Notch activation directly engages gamma-secretase and subsequently leads to diminished PS1 expression, suggesting a complex set of feedback interactions following Notch activation...
  13. pmc Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy
    Tara L Spires
    Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 25:7278-87. 2005
    ..Decreased spine density will likely contribute to altered neural system function and behavioral impairments observed in Tg2576 mice...
  14. pmc Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation
    Hai Yan Wu
    Department of Neurology Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 30:2636-49. 2010
    ..Thus, Abeta appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades...
  15. ncbi request reprint Ubiquilin 1 modulates amyloid precursor protein trafficking and Abeta secretion
    Mikko Hiltunen
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
    J Biol Chem 281:32240-53. 2006
    ..These findings suggest that changes in UBQLN1 steady-state levels affect APP trafficking and processing, thereby influencing the generation of Abeta...
  16. ncbi request reprint TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation
    Pamela J McLean
    Alzheimer s Disease Research Unit, Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital East, Charlestown, Massachusetts 02129, USA
    J Neurochem 83:846-54. 2002
    ..Moreover, these data support a role for chaperone proteins, including torsinA and heat shock proteins, in cellular responses to neurodegenerative inclusions...
  17. ncbi request reprint Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy
    Brian J Bacskai
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 22:7873-8. 2002
    ..Together, these results indicate that clearance of amyloid deposits in vivo may involve, in addition to Fc-dependent clearance, a non-Fc-mediated disruption of plaque structure...
  18. ncbi request reprint Activated Notch1 associates with a presenilin-1/gamma-secretase docking site
    Pavan Ramdya
    Alzheimer s Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurochem 87:843-50. 2003
    ..These results suggest a novel mechanism of ligand binding-mediated signal transduction of Notch1...
  19. ncbi request reprint Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease
    Tiago Fleming Outeiro
    Alzheimer s Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA
    Science 317:516-9. 2007
    ..Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging...
  20. ncbi request reprint Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein
    Michael C Irizarry
    Alzheimer Disease Research Unit, Massachusetts General Hospital East, Charlestown, Massachusetts, USA
    J Neurochem 90:1132-43. 2004
    ..The apoE modulation of Abeta production and APP signaling is a potential mechanism affecting Alzheimer disease risk...
  21. pmc Passive immunotherapy rapidly increases structural plasticity in a mouse model of Alzheimer disease
    Tara L Spires-Jones
    MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Charlestown, MA, USA
    Neurobiol Dis 33:213-20. 2009
    ..These data support the hypothesis that removing toxic soluble forms of amyloid-beta rapidly increases structural plasticity possibly allowing functional recovery of neural circuits...
  22. pmc A single dose of passive immunotherapy has extended benefits on synapses and neurites in an Alzheimer's disease mouse model
    Anete Rozkalne
    MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Charlestown, MA 02129, USA
    Brain Res 1280:178-85. 2009
    ....
  23. ncbi request reprint An alternatively spliced form of rodent alpha-synuclein forms intracellular inclusions in vitro: role of the carboxy-terminus in alpha-synuclein aggregation
    Pamela J McLean
    Alzheimer s Disease Research Unit, Center for Aging, Genetics and Neurodegeneration, Massachusetts General Hospital East, 114 16th Street, Charlestown, MA 02129, USA
    Neurosci Lett 323:219-23. 2002
    ....
  24. pmc Beneficial effect of human anti-amyloid-beta active immunization on neurite morphology and tau pathology
    Alberto Serrano-Pozo
    MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Massachusetts Alzheimer Disease Research Center, Harvard Medical School, Building 114, 16th Street, Charlestown, MA 02129 4404, USA
    Brain 133:1312-27. 2010
    ....
  25. ncbi request reprint In vivo imaging of reactive oxygen species specifically associated with thioflavine S-positive amyloid plaques by multiphoton microscopy
    Megan E McLellan
    Massachusetts General Hospital, Department of Neurology Alzheimer s Disease Research Laboratory, Charlestown, Massachusetts 02129, USA
    J Neurosci 23:2212-7. 2003
    ..Antioxidant therapy neutralizes these highly reactive molecules and may therefore be of therapeutic value in Alzheimer's disease...
  26. ncbi request reprint Motor dysfunction and gliosis with preserved dopaminergic markers in human alpha-synuclein A30P transgenic mice
    Teresa Gomez-Isla
    Department of Neurology, University of Minnesota, Minneapolis, MN 55455, USA
    Neurobiol Aging 24:245-58. 2003
    ..Thus, high expression of mutant human alpha-synuclein resulted in a progressive motor and widespread CNS gliotic phenotype independent of dopaminergic dysfunction in the Tg5093 line...
  27. pmc Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport
    Will Stoothoff
    MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurochem 111:417-27. 2009
    ..Our results indicate that tau-induced changes in axonal transport may be an underlying theme in neurodegenerative diseases associated with isoform specific changes in tau's interaction with microtubules...
  28. ncbi request reprint Expression of APP pathway mRNAs and proteins in Alzheimer's disease
    Toshifumi Matsui
    Alzheimer Disease Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Brain Res 1161:116-23. 2007
    ..These results suggest that altered transcription of APP in AD is proportionately associated with Abeta peptide, may occur in the context of gliosis, and may contribute to Abeta deposition in sporadic AD...
  29. pmc Allosteric modulation of PS1/gamma-secretase conformation correlates with amyloid beta(42/40) ratio
    Kengo Uemura
    Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    PLoS ONE 4:e7893. 2009
    ..Many modulators of gamma-secretase function have been described. We hypothesize that these modulators act by a common mechanism by allosterically modifying the structure of presenilin...
  30. pmc Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease
    Melanie Meyer-Luehmann
    Alzheimer s Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    Nature 451:720-4. 2008
    ..Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology...
  31. pmc Impaired spine stability underlies plaque-related spine loss in an Alzheimer's disease mouse model
    Tara L Spires-Jones
    MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital Harvard Medical School, Charlestown, Massachusetts, USA
    Am J Pathol 171:1304-11. 2007
    ..These data show a small population of rapidly changing spines in adult and even elderly mouse cortex; further, in the vicinity of amyloid plaques, spine stability is markedly impaired leading to loss of synaptic structural integrity...
  32. ncbi request reprint Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease
    Elissa M Robbins
    MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 26:365-71. 2006
    ..35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions...
  33. pmc Tangle-bearing neurons survive despite disruption of membrane integrity in a mouse model of tauopathy
    Alix de Calignon
    MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neuropathol Exp Neurol 68:757-61. 2009
    ..This unique combination of in vivo multiphoton imaging with markers of cell death and pathological alteration is a powerful tool for investigating neuronal damage associated with neurofibrillary pathology...
  34. ncbi request reprint Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra
    Jessie L St Martin
    Alzheimer s Disease Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurochem 100:1449-57. 2007
    ....
  35. ncbi request reprint BACE is degraded via the lysosomal pathway
    Young Ho Koh
    Genetics and Aging Research Unit, Massachusetts General Hospital, Charlestown, 02129, USA
    J Biol Chem 280:32499-504. 2005
    ..Collectively, our data indicate that BACE is transported to the late endosomal/lysosomal compartments where it is degraded via the lysosomal pathway and that the di-leucine motif plays a role in sorting BACE to lysosomes...
  36. ncbi request reprint Demonstration of BACE (beta-secretase) phosphorylation and its interaction with GGA1 in cells by fluorescence-lifetime imaging microscopy
    Christine A F von Arnim
    Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA
    J Cell Sci 117:5437-45. 2004
    ....
  37. ncbi request reprint The gamma secretase-generated carboxyl-terminal domain of the amyloid precursor protein induces apoptosis via Tip60 in H4 cells
    Ayae Kinoshita
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Biol Chem 277:28530-6. 2002
    ..Thus, gamma secretase cleavage of APP may contribute to Alzheimer's disease-related neurodegeneration in two ways: release of amyloid-beta and liberation of a bioactive carboxyl-terminal domain from membrane-bound APP...
  38. ncbi request reprint Coordinated expression of caspase 8, 3 and 7 mRNA in temporal cortex of Alzheimer disease: relationship to formic acid extractable abeta42 levels
    Toshifumi Matsui
    Alzheimer Research Unit, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neuropathol Exp Neurol 65:508-15. 2006
    ..Thus, a principal caspase pathway from caspase-8 to caspase-3 and/or 7 may contribute to neuron loss in AD brain...
  39. ncbi request reprint Amyloid-beta antibody treatment leads to rapid normalization of plaque-induced neuritic alterations
    Julianne A Lombardo
    Center for Aging, Genetics, and Neurodegeneration, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 23:10879-83. 2003
    ..Moreover, the rapid normalization of neuritic dystrophy suggests an unexpected degree of plasticity in the adult nervous system...
  40. ncbi request reprint GROalpha/KC, a chemokine receptor CXCR2 ligand, can be a potent trigger for neuronal ERK1/2 and PI-3 kinase pathways and for tau hyperphosphorylation-a role in Alzheimer's disease?
    MengQi Xia
    Alzheimer s Research Unit, CAGN 2009, Department of Neurology, Massachusetts General Hospital East, Harvard Medical School, 144 16th Street, Charlestown, MA, USA
    J Neuroimmunol 122:55-64. 2002
    ..GROalpha immunoreactivity can be detected in a subpopulation of neurons in normal and AD. Therefore, the CXCR2-ligand pair may have a potent pathophysiological role in neurodegenerative diseases...
  41. pmc Preservation of neuronal number despite age-related cortical brain atrophy in elderly subjects without Alzheimer disease
    Stefanie H Freeman
    C S Kubik Laboratory for Neuropathology, Department of Pathology, Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
    J Neuropathol Exp Neurol 67:1205-12. 2008
    ..These data suggest that loss of neuronal and dendritic architecture, rather than loss of neurons, underlies neocortical volume loss with increasing age in the absence of Alzheimer disease...
  42. ncbi request reprint GGA1 acts as a spatial switch altering amyloid precursor protein trafficking and processing
    Christine A F von Arnim
    Alzheimer Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 26:9913-22. 2006
    ..GGA1 may act as a specific spatial switch influencing APP trafficking and processing, so that APP-GGA1 interactions may have pathophysiological relevance in AD...
  43. ncbi request reprint Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer's disease patients
    Robert D Moir
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129 4404, USA
    J Biol Chem 280:17458-63. 2005
    ..041) with plasma immunoreactivity to CAPS. These data suggest that autoantibodies to CAPS are depleted in AD patients and raise the prospect that immunization with anti-CAPS antibodies might provide therapeutic benefit for AD...
  44. pmc Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase
    Lauren Herl
    Alzheimer Research Unit, MassGeneral Institute for Neurodegenerative, Diseases, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Mol Cell Neurosci 41:166-74. 2009
    ..Mutant APP affects both intracellular location and efficiency of APP-PS1 interactions, thereby changing the Abeta(42/40) ratio...
  45. ncbi request reprint No alteration in tau exon 10 alternative splicing in tangle-bearing neurons of the Alzheimer's disease brain
    Martin Ingelsson
    Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Acta Neuropathol 112:439-49. 2006
    ..In conclusion, this study indicated region-specific and possibly cell-type-specific tau splicing but did not lend any support to overt changes in alternative splicing of tau exon 10 being an underlying factor in AD pathogenesis...
  46. pmc A limited role for microglia in antibody mediated plaque clearance in APP mice
    Monica Garcia-Alloza
    Massachusetts General Hospital, Department of Neurology Alzheimer s Disease Research Laboratory, 114 16th Street, 2010, Charlestown, MA 02129, USA
    Neurobiol Dis 28:286-92. 2007
    ....
  47. pmc Abeta plaques lead to aberrant regulation of calcium homeostasis in vivo resulting in structural and functional disruption of neuronal networks
    KISHORE V KUCHIBHOTLA
    Massachusetts General Hospital, Department of Neurology Alzheimer s Disease Research Laboratory, 114 16th Street, Charlestown, MA 02129, USA
    Neuron 59:214-25. 2008
    ..Together, these data demonstrate that senile plaques impair neuritic calcium homeostasis in vivo and result in the structural and functional disruption of neuronal networks...
  48. pmc CHIP targets toxic alpha-Synuclein oligomers for degradation
    Julie E Tetzlaff
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
    J Biol Chem 283:17962-8. 2008
    ....
  49. ncbi request reprint APP substitutions V715F and L720P alter PS1 conformation and differentially affect Abeta and AICD generation
    Giuseppina Tesco
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, Massachusetts 02129 4404, USA
    J Neurochem 95:446-56. 2005
    ..In conclusion, both APPV715F and APPL720P change PS1 conformation with differential effects on Abeta and AICD production...
  50. ncbi request reprint Single molecule profiling of tau gene expression in Alzheimer's disease
    Chris Conrad
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease MIND, Charlestown, Massachusetts, USA
    J Neurochem 103:1228-36. 2007
    ..Furthermore, splicing-based therapeutics is an emerging area of drug development, and a well-defined and quantitative assay for monitoring single-gene transcriptome will be relevant for such development...
  51. pmc Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice
    KISHORE V KUCHIBHOTLA
    Massachusetts General Hospital, Department of Neurology Alzheimer s Disease Research Laboratory, 114 16th Street, Charlestown, MA 02129, USA
    Science 323:1211-5. 2009
    ..Thus, although neurotoxicity is observed near amyloid-beta deposits, there exists a more general astrocyte-based network response to focal pathology...
  52. ncbi request reprint Increase in the relative expression of tau with four microtubule binding repeat regions in frontotemporal lobar degeneration and progressive supranuclear palsy brains
    Martin Ingelsson
    Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Acta Neuropathol 114:471-9. 2007
    ..In conclusion, we demonstrated increased but largely variable 4R tau/3R tau mRNA ratios in FTLD and PSP cases, suggesting heterogeneous pathophysiological processes within these disorders...
  53. ncbi request reprint Neuritic alterations and neural system dysfunction in Alzheimer's disease and dementia with Lewy bodies
    J Klucken
    Alzheimer s Disease Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts, USA
    Neurochem Res 28:1683-91. 2003
    ..Thus both classic neuropathological changes and cellular dysfunctions might contribute to the cognitive impairments in AD and DLB...
  54. ncbi request reprint Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's disease
    Jean C Augustinack
    Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown 02129, USA
    Acta Neuropathol 103:26-35. 2002
    ..The sequence of early tau phosphorylation suggests that there are events prior to filament formation that are specific to particular phosphorylated tau epitopes, leading to conformational changes and cytopathological alterations...
  55. ncbi request reprint Family-based association between Alzheimer's disease and variants in UBQLN1
    Lars Bertram
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown 02129, USA
    N Engl J Med 352:884-94. 2005
    ..The gene encoding ubiquilin 1 (UBQLN1) is one of several candidate genes for Alzheimer's disease located near a well-established linkage peak on chromosome 9q22...
  56. ncbi request reprint Reversible memory loss in a mouse transgenic model of Alzheimer's disease
    Linda A Kotilinek
    Department of Neurology, University of Minnesota, Minneapolis 55455, USA
    J Neurosci 22:6331-5. 2002
    ..If these Abeta assemblies contribute significantly to memory loss in AD, then successfully targeting them might improve memory in some AD patients...
  57. ncbi request reprint Decreased levels of BDNF protein in Alzheimer temporal cortex are independent of BDNF polymorphisms
    Jung Lee
    Harvard Medical School, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Exp Neurol 194:91-6. 2005
    ..The results suggest that the investigated BDNF polymorphisms are neither robust genetic risk factors nor determinants of BDNF protein levels in AD...
  58. ncbi request reprint Interaction between presenilin 1 and ubiquilin 1 as detected by fluorescence lifetime imaging microscopy and a high-throughput fluorescent plate reader
    Anne V Thomas
    Alzheimer s Disease Research Laboratory, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Biol Chem 281:26400-7. 2006
    ....
  59. pmc Dopamine-induced conformational changes in alpha-synuclein
    Tiago F Outeiro
    MassGeneral Institute for Neurodegenerative Disease, Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
    PLoS ONE 4:e6906. 2009
    ..A number of in vitro studies showed that dopamine can modulate the aggregation of alpha-synuclein by inhibiting the formation of or by disaggregating amyloid fibrils [5], [6], [7]...
  60. pmc Amyloid deposition is associated with impaired default network function in older persons without dementia
    Reisa A Sperling
    Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Neuron 63:178-88. 2009
    ....
  61. pmc Formation of toxic oligomeric alpha-synuclein species in living cells
    Tiago Fleming Outeiro
    Alzheimer s Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH Harvard Medical School, Charlestown, Massachusetts, United States of America
    PLoS ONE 3:e1867. 2008
    ..However, to date, oligomeric species have not been identified in living cells...
  62. ncbi request reprint Hsp70 Reduces alpha-Synuclein Aggregation and Toxicity
    Jochen Klucken
    Alzheimer s Disease Research Laboratory, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Biol Chem 279:25497-502. 2004
    ..Taken together, these data demonstrate that the molecular chaperone Hsp70 can reduce the amount of misfolded, aggregated alpha-synuclein species in vivo and in vitro and protect it from alpha-synuclein-dependent toxicity...
  63. pmc Four-dimensional multiphoton imaging of brain entry, amyloid binding, and clearance of an amyloid-beta ligand in transgenic mice
    Brian J Bacskai
    Department of Neurology Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, 114 16th Street, Charlestown, MA 02129, USA
    Proc Natl Acad Sci U S A 100:12462-7. 2003
    ..WT mice showed rapid brain entry and clearance of PIB without any binding. These results demonstrate that the compound PIB has the properties required for a good amyloid-imaging agent in humans with or at risk for AD...
  64. ncbi request reprint Detection of novel intracellular alpha-synuclein oligomeric species by fluorescence lifetime imaging
    Jochen Klucken
    MassGeneral Institute for Neurodegenerative Disease, Alzheimer s Disease Research Unit, Massachusetts General Hospital, 114 16 St, Charlestown, MA 02129, USA
    FASEB J 20:2050-7. 2006
    ..Thus, the neuroprotective effect of Hsp70 can be explained by its chaperone activity on alpha-synuclein molecules, rather than alteration of alpha-synuclein-alpha-synuclein interactions...
  65. ncbi request reprint Neuronal structure is altered by amyloid plaques
    Tara L Spires
    Department of Neurology, Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Rev Neurosci 15:267-78. 2004
    ....
  66. ncbi request reprint Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+-induced cytotoxicity in Parkinson's disease in vitro models
    Tiago Fleming Outeiro
    Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Bldg 114 3300, 16th St, Charlestown, MA 02129 4404, USA
    Biochem Biophys Res Commun 357:596-602. 2007
    ..Further, our results suggest a rationale for the development of highly potent, bio-available, brain-penetrable PARP-1 inhibitors to provide therapeutic benefits for Parkinson's patients...
  67. pmc Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses' health study
    Francine Grodstein
    Channing Laboratory, Department of Medicine, Brigham and Women s Hospital, and Harvard Medical School, Boston, Massachusetts, USA
    PLoS ONE 3:e1590. 2008
    ..Since telomeres shorten with age and oxidative stress, both of which are important contributors to the onset of dementia, telomere length might be a valuable biomarker...
  68. pmc Plasma amyloid beta-protein and C-reactive protein in relation to the rate of progression of Alzheimer disease
    Joseph J Locascio
    Massachusetts Alzheimer s Disease Research Center, Wang Ambulatory Care Center, Suite 720, Room 731 G, Massachusetts General Hospital, 15 Parkman St, Boston, MA 02114, USA
    Arch Neurol 65:776-85. 2008
    ....
  69. pmc The Alzheimer's disease-associated amyloid beta-protein is an antimicrobial peptide
    Stephanie J Soscia
    Genetics and Aging Research Unit, Mass General Institute for Neurodegenerative Disease and Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America
    PLoS ONE 5:e9505. 2010
    ....
  70. ncbi request reprint Amyloid precursor protein associates with a nicastrin-dependent docking site on the presenilin 1-gamma-secretase complex in cells demonstrated by fluorescence lifetime imaging
    Oksana Berezovska
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 23:4560-6. 2003
    ..We interpret these results to suggest that there is a noncatalytic docking site closely associated with PS1-gamma-secretase...
  71. pmc Uniform polarity microtubule assemblies imaged in native brain tissue by second-harmonic generation microscopy
    Daniel A Dombeck
    School of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853, USA
    Proc Natl Acad Sci U S A 100:7081-6. 2003
    ..SHG imaging provides a tool to investigate the kinetics and function of MT ensemble polarity in dynamic native brain tissue structures and other subcellular motility structures based on polarized MTs...
  72. ncbi request reprint Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques
    Edward A Stern
    MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 24:4535-40. 2004
    ..Our results show that plaques disrupt the synchrony of convergent inputs, reducing the ability of neurons to successfully integrate and propagate information...
  73. ncbi request reprint Molecular dissection of the interaction between amyloid precursor protein and its neuronal trafficking receptor SorLA/LR11
    Olav M Andersen
    Max Delbrueck Center for Molecular Medicine, Berlin, 13125 Berlin, Germany
    Biochemistry 45:2618-28. 2006
    ..These data shed new light on the molecular determinants of neuronal APP trafficking and processing and on possible targets for intervention with senile plaque formation in patients with AD...
  74. ncbi request reprint Imaging Abeta plaques in living transgenic mice with multiphoton microscopy and methoxy-X04, a systemically administered Congo red derivative
    William E Klunk
    Department of Psychiatry, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA
    J Neuropathol Exp Neurol 61:797-805. 2002
    ....
  75. ncbi request reprint A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain
    Chester A Mathis
    PET Facility, Department of Radiology, University of Pittsburgh, PA 15213, USA
    Bioorg Med Chem Lett 12:295-8. 2002
    ..Amyloid deposits were imaged with multiphoton microscopy in the brains of living transgenic mice following the systemic injection of unlabeled 6. [(11)C]6 is a promising amyloid imaging agent for Alzheimer's disease...
  76. pmc Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy
    Tara L Spires
    Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown 02129, USA
    Am J Pathol 168:1598-607. 2006
    ..Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death...
  77. ncbi request reprint Familial Alzheimer's disease presenilin 1 mutations cause alterations in the conformation of presenilin and interactions with amyloid precursor protein
    Oksana Berezovska
    Alzheimer Research Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neurosci 25:3009-17. 2005
    ..We propose that the conformational change we observed may therefore provide a shared molecular mechanism for FAD pathogenesis caused by a wide range of PS1 mutations...
  78. pmc Visualizing interaction of proteins relevant to Alzheimer's disease in intact cells
    Anne V Thomas
    Department of Neurology, University of Cologne, Germany
    Methods 44:299-303. 2008
    ....
  79. pmc Small heat shock proteins protect against alpha-synuclein-induced toxicity and aggregation
    Tiago Fleming Outeiro
    Alzheimer s Research Unit, MassGeneral Institute for Neurodegenerative Disease, MGH, Harvard Medical School, Charlestown, MA 02129, USA
    Biochem Biophys Res Commun 351:631-8. 2006
    ..In addition, intracellular inclusions were immunopositive for endogenous Hsp27, and overexpression of this protein reduced aSyn aggregation in a cell culture model...
  80. doi request reprint In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons
    Tara L Spires-Jones
    MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA
    J Neurosci 28:862-7. 2008
    ....
  81. ncbi request reprint TAR-DNA binding protein 43 in Pick disease
    Stefanie H Freeman
    Department of Pathology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA
    J Neuropathol Exp Neurol 67:62-7. 2008
    ....
  82. ncbi request reprint Low density lipoprotein receptor-related protein (LRP) interacts with presenilin 1 and is a competitive substrate of the amyloid precursor protein (APP) for gamma-secretase
    Alberto Lleo
    Alzheimer Research Unit, Massachusetts Institute for Neurodegenerative Disorders, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Biol Chem 280:27303-9. 2005
    ..In conclusion, LRP is a PS1 interactor and can compete with APP for gamma-secretase enzymatic activity...
  83. ncbi request reprint Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria
    Piera Pasinelli
    Day Laboratory for Neuromuscular Research, Department of Neurology, Harvard Medical School, Mass General Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Neuron 43:19-30. 2004
    ..These findings provide new insights into the anti-apoptotic function of SOD1 and suggest that entrapment of Bcl-2 by large SOD1 aggregates may deplete motor neurons of this anti-apoptotic protein...
  84. ncbi request reprint Molecular imaging with Pittsburgh Compound B confirmed at autopsy: a case report
    Brian J Bacskai
    MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Charlestown, MA 02129, USA
    Arch Neurol 64:431-4. 2007
    ..Imaging revealed marked region specific binding of PiB and abnormal fluorodeoxyglucose uptake. Intervention Autopsy was performed 3 months after the PiB scan...
  85. ncbi request reprint Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo
    Tudor A Fulga
    Department of Pathology, Brigham and Women s Hospital and Harvard Medical School, Harvard New Research Building Room 652, 77 Louis Pasteur Avenue, Boston, MA 02115, USA
    Nat Cell Biol 9:139-48. 2007
    ..These findings raise the possibility that a direct interaction between tau and actin may be a critical mediator of tau-induced neurotoxicity in Alzheimer's disease and related disorders...
  86. ncbi request reprint Monitoring proteins in intact cells
    Oksana Berezovska
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
    Sci Aging Knowledge Environ 2003:PE14. 2003
    ..This approach may have widespread applicability in studies of neurodegenerative disease mechanisms...
  87. ncbi request reprint Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model
    Monica Garcia-Alloza
    Department of Neurology Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA
    J Neuropathol Exp Neurol 65:1082-9. 2006
    ..The quantitative ex vivo screen combined with in vivo monitoring of efficacy should lead to more effective clinical therapies for the prevention of oxidative stress and neurotoxicity in AD...
  88. ncbi request reprint Alzheimer's disease: what multiphoton microscopy teaches us
    Brian J Bacskai
    Alzheimer s Disease Research Laboratory, Massachusetts General Hospital, Charlestown 02129, USA
    Neuroscientist 8:386-90. 2002
    ..This in vivo imaging approach allows direct examination of the natural history of plaques and evaluation of antiplaque therapeutics in mouse models of the disease...

Research Grants31

  1. Neurologic Alterations in Alzheimer's Disease
    Bradley T Hyman; Fiscal Year: 2010
    ..We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies. ..
  2. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2006
    ..We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies. ..
  3. LRP AND ALZHEIMER'S DISEASE
    Bradley Hyman; Fiscal Year: 2007
    ..Description, ..
  4. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2007
    ..We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies. ..
  5. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2009
    ..We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies. ..
  6. Neurologic Alterations in Alzheimer's Disease
    Bradley Hyman; Fiscal Year: 2009
    ..We believe that the questions posed in this application have high clinical relevance, and the severity and prevalence of the disease add urgency to these studies. ..
  7. Anatomical Changes in Tau Transgenic Models
    Bradley T Hyman; Fiscal Year: 2010
    ..Based on these results, therapies aimed at reducing the damage done by neurofibrillary tangles will be explored, in an attempt to better understand what causes the damage and how to prevent it. ..
  8. NEUROPATHOLOGICAL ALTERATIONS IN ALZHEIMERS DISEASE
    Bradley Hyman; Fiscal Year: 1999
    ..In sum, we will develop and use quantitative techniques and analyses in order to test new hypotheses about the structure organization of the normal human cerebral cortex and the specific alterations that occur in AD. ..
  9. NEUROPATHOLOGICAL ALTERATIONS IN ALZHEIMERS DISEASE
    Bradley Hyman; Fiscal Year: 1999
    ..In sum, we will develop and use quantitative techniques and analyses in order to test new hypotheses about the structure organization of the normal human cerebral cortex and the specific alterations that occur in AD. ..
  10. Anatomical changes in tau trangenic models
    Bradley T Hyman; Fiscal Year: 2010
    ..The results will have direct impact on design of therapeutic agents destined for clinical trials. ..