amyloid beta protein

Summary

Summary: A 4-kDa protein, 39-43 amino acids long, expressed by a gene located on chromosome 21. It is the major protein subunit of the vascular and plaque amyloid filaments in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The protein is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.

Top Publications

  1. ncbi Alzheimer's disease is a synaptic failure
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, and the Harvard Center for Neurodegeneration and Repair, Boston, MA 02115, USA
    Science 298:789-91. 2002
  2. ncbi Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
    E H Corder
    Department of Medicine, Joseph and Kathleen Bryan Alzheimer s Disease Research Center, Duke University Medical Center, Durham, NC 27710
    Science 261:921-3. 1993
  3. ncbi Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo
    Dominic 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
  4. ncbi Alzheimer's disease: genes, proteins, and therapy
    D J Selkoe
    Department of Neurology and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
    Physiol Rev 81:741-66. 2001
  5. ncbi Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
    Rakez Kayed
    Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697 3900, USA
    Science 300:486-9. 2003
  6. ncbi A specific amyloid-beta protein assembly in the brain impairs memory
    Sylvain Lesne
    Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
    Nature 440:352-7. 2006
  7. ncbi Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
    R Vassar
    Amgen, Inc, One Amgen Center Drive, M S 29 2 B, Thousand Oaks, CA 91320 1799, USA
    Science 286:735-41. 1999
  8. ncbi Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function
    James P Cleary
    Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417, USA
    Nat Neurosci 8:79-84. 2005
  9. ncbi Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
    Rudolph E Tanzi
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachussetts General Hospital, Harvard Medical School, Charlestown, Massachussetts 02129, USA
    Cell 120:545-55. 2005
  10. ncbi The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
    John Hardy
    Laboratories of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA
    Science 297:353-6. 2002

Detail Information

Publications275 found, 100 shown here

  1. ncbi Alzheimer's disease is a synaptic failure
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, and the Harvard Center for Neurodegeneration and Repair, Boston, MA 02115, USA
    Science 298:789-91. 2002
    ..suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.
  2. ncbi Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
    E H Corder
    Department of Medicine, Joseph and Kathleen Bryan Alzheimer s Disease Research Center, Duke University Medical Center, Durham, NC 27710
    Science 261:921-3. 1993
    ..Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80...
  3. ncbi Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo
    Dominic 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
    Although extensive data support a central pathogenic role for amyloid beta protein (Abeta) in Alzheimer's disease, the amyloid hypothesis remains controversial, in part because a specific neurotoxic species of Abeta and the nature of its ..
  4. ncbi Alzheimer's disease: genes, proteins, and therapy
    D J Selkoe
    Department of Neurology and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, USA
    Physiol Rev 81:741-66. 2001
    ..The progress reviewed here, coupled with better ability to diagnose the disease early, bode well for the successful development of therapeutic and preventative drugs for this major public health problem...
  5. ncbi Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis
    Rakez Kayed
    Department of Molecular Biology and Biochemistry, University of California, Irvine, CA 92697 3900, USA
    Science 300:486-9. 2003
    ..These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity...
  6. ncbi A specific amyloid-beta protein assembly in the brain impairs memory
    Sylvain Lesne
    Department of Neurology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA
    Nature 440:352-7. 2006
    ..We propose that Abeta*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease...
  7. ncbi Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE
    R Vassar
    Amgen, Inc, One Amgen Center Drive, M S 29 2 B, Thousand Oaks, CA 91320 1799, USA
    Science 286:735-41. 1999
    ..Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease...
  8. ncbi Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function
    James P Cleary
    Geriatric Research, Education and Clinical Center, Minneapolis Veterans Affairs Medical Center, Minneapolis, Minnesota 55417, USA
    Nat Neurosci 8:79-84. 2005
    ....
  9. ncbi Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective
    Rudolph E Tanzi
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Diseases, Department of Neurology, Massachussetts General Hospital, Harvard Medical School, Charlestown, Massachussetts 02129, USA
    Cell 120:545-55. 2005
    ..Here we assess the amyloid hypothesis based on both known and putative Alzheimer's disease genes...
  10. ncbi The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
    John Hardy
    Laboratories of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA
    Science 297:353-6. 2002
    ..The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance...
  11. ncbi Synaptic targeting by Alzheimer's-related amyloid beta oligomers
    Pascale N Lacor
    Neurobiology and Physiology Department, Northwestern University, Evanston, Illinois 60208, USA5
    J Neurosci 24:10191-200. 2004
    ..Results suggest the hypothesis that targeting and functional disruption of particular synapses by Abeta oligomers may provide a molecular basis for the specific loss of memory function in early AD...
  12. ncbi Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse
    D Schenk
    Elan Pharmaceuticals, South San Francisco, California 94080, USA
    Nature 400:173-7. 1999
    ..Our results raise the possibility that immunization with amyloid-beta may be effective in preventing and treating Alzheimer's disease...
  13. ncbi The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
    J Kang
    Nature 325:733-6. 1987
    ..This sequence, together with the localization of its gene on chromosome 21, suggests that the cerebral amyloid deposited in Alzheimer's disease and aged Down's syndrome is caused by aberrant catabolism of a cell-surface receptor...
  14. ncbi Bone marrow-derived microglia play a critical role in restricting senile plaque formation in Alzheimer's disease
    Alain R Simard
    Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Laval University, 2705 Laurier Boul, Quebec G1V 4G2, Canada
    Neuron 49:489-502. 2006
    ..Therapeutic strategies aiming to improve their recruitment could potentially lead to a new powerful tool for the elimination of toxic senile plaques...
  15. ncbi Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model
    Erik D Roberson
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Science 316:750-4. 2007
    ..Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions...
  16. ncbi Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease
    T Kawarabayashi
    Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA
    J Neurosci 21:372-81. 2001
    The accumulation of amyloid beta protein (Abeta) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry...
  17. ncbi A beta oligomers - a decade of discovery
    Dominic 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...
  18. ncbi The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation
    C Nilsberth
    Karolinska Institutet, Department of Neurotec, Geriatric Medicine, Novum KFC, S 141 86 Huddinge, Sweden
    Nat Neurosci 4:887-93. 2001
    ....
  19. ncbi Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease
    Pascale N Lacor
    Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA
    J Neurosci 27:796-807. 2007
    ..The observed disruption of dendritic spines links ADDLs to a major facet of AD pathology, providing strong evidence that ADDLs in AD brain cause neuropil damage believed to underlie dementia...
  20. pmc Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory
    Ganesh 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...
  21. ncbi Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease
    F Bard
    Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, California 94080, USA
    Nat Med 6:916-9. 2000
    ....
  22. pmc Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease
    W Haung Yu
    Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA
    J Cell Biol 171:87-98. 2005
    ..Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD...
  23. pmc Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake
    Shaomin Li
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Neuron 62:788-801. 2009
    ..In accord, synaptic glutamate uptake was significantly decreased by soluble Abeta. We conclude that soluble Abeta oligomers perturb synaptic plasticity by altering glutamate recycling at the synapse and promoting synapse depression...
  24. ncbi Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease
    Jorge J Palop
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Neuron 55:697-711. 2007
    ..Aberrant increases in network excitability and compensatory inhibitory mechanisms in the hippocampus may contribute to Abeta-induced neurological deficits in hAPP mice and, possibly, also in humans with AD...
  25. ncbi beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis
    C K Combs
    Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
    J Neurosci 21:1179-88. 2001
    ..This study demonstrates a functional linkage between beta-amyloid-dependent activation of microglia and several characteristic markers of neuronal death occurring in Alzheimer's disease brains...
  26. pmc Pathways towards and away from Alzheimer's disease
    Mark P Mattson
    Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 5600 Nathan Shock Drive, Baltimore, Maryland 21224, USA
    Nature 430:631-9. 2004
    ..But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies...
  27. pmc Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons
    M Simons
    Cell Biology Programme, European Molecular Biology Laboratory, Meyerhofstrasse 1, Postfach 10 2209, D 69012 Heidelberg, Germany
    Proc Natl Acad Sci U S A 95:6460-4. 1998
    ..Our results show that cholesterol is required for Abeta formation to occur and imply a link between cholesterol, Abeta, and Alzheimer's disease...
  28. pmc Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease
    R B DeMattos
    The Center for the Study of Nervous System Injury, Washington University School of Medicine, 660 South Euclid Avenue, Box 8111, St. Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 98:8850-5. 2001
    ..Although peripheral administration of m266 to PDAPP mice markedly reduces A beta deposition, m266 did not bind to A beta deposits in the brain. Thus, m266 appears to reduce brain A beta burden by altering CNS and plasma A beta clearance...
  29. ncbi APP processing and synaptic function
    Flavio Kamenetz
    Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
    Neuron 37:925-37. 2003
    ..Disruption of this feedback system could contribute to disease progression in AD...
  30. ncbi Oxidative damage is the earliest event in Alzheimer disease
    A Nunomura
    Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Neuropathol Exp Neurol 60:759-67. 2001
    ..These findings suggest that AD is associated with compensatory changes that reduce damage from reactive oxygen...
  31. pmc A structural model for Alzheimer's beta -amyloid fibrils based on experimental constraints from solid state NMR
    Aneta T Petkova
    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 0520, USA
    Proc Natl Acad Sci U S A 99:16742-7. 2002
    ..The only charged sidechains in the core are those of D23 and K28, which form salt bridges. Fibrils with minimum mass-per-length and diameter consist of two cross-beta units with their hydrophobic faces juxtaposed...
  32. ncbi Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report
    James A R Nicoll
    Division of Clinical Neurosciences, University of Southampton, Southampton, UK
    Nat Med 9:448-52. 2003
    ..The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9)...
  33. ncbi Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability
    Karie N Dahlgren
    Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, Illinois 60201, USA
    J Biol Chem 277:32046-53. 2002
    ....
  34. pmc Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior
    Dennis J Selkoe
    Center for Neurologic Diseases, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Behav Brain Res 192:106-13. 2008
    ..A new diagnostic-therapeutic paradigm to successfully address AD and its harbinger, mild cognitive impairment-amnestic type, is emerging...
  35. ncbi Neurovascular mechanisms of Alzheimer's neurodegeneration
    Berislav V Zlokovic
    Frank P Smith Laboratories for Neuroscience and Neurological Surgery Research, Department of Neurological Surgery and Division of Neurovascular Biology, University of Rochester Medical Center, Rochester, NY 14642, USA
    Trends Neurosci 28:202-8. 2005
    ....
  36. pmc Amyloid beta -protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways
    Gal Bitan
    Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 100:330-5. 2003
    ..The strong etiologic association of Abeta42 with AD may thus be a result of assemblies formed at the earliest stages of peptide oligomerization...
  37. ncbi Globular amyloid beta-peptide oligomer - a homogenous and stable neuropathological protein in Alzheimer's disease
    Stefan Barghorn
    Neuroscience Discovery Research, Abbott GmbH and Co KG, Ludwigshafen, Germany
    J Neurochem 95:834-47. 2005
    ..Selective neutralization of the Abeta globulomer structure epitope is expected to have a high potential for treatment of AD...
  38. pmc Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease
    Koichi Iijima
    Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
    Proc Natl Acad Sci U S A 101:6623-8. 2004
    ..Moreover, Drosophila may serve as a model for facilitating the understanding of molecular mechanisms underlying Abeta toxicity and the discovery of novel therapeutic targets for AD...
  39. ncbi Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP
    J Lewis
    Birdsall Building, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA
    Science 293:1487-91. 2001
    ..The interaction between Abeta and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease...
  40. ncbi Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization
    J M Orgogozo
    Federation of Neurology, CHU Pellegrin, Bordeaux, France
    Neurology 61:46-54. 2003
    ..A Phase I study in AD patients demonstrated good safety and tolerability of multiple injections of aggregated Abeta42 (AN1792) with QS-21 as adjuvant...
  41. ncbi A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease
    D Morgan
    Department of Pharmacology, University of South Florida, Tampa 33612, USA
    Nature 408:982-5. 2000
    ..The A beta-vaccinated mice also had a partial reduction in amyloid burden at the end of the study. This therapeutic approach may thus prevent and, possibly, treat Alzheimer's dementia...
  42. ncbi Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease
    Joseph El Khoury
    Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, Massachusetts 02129, USA
    Nat Med 13:432-8. 2007
    ..Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance...
  43. ncbi Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway
    Ganesh 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...
  44. ncbi Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase
    Andrey Y Abramov
    Mitochondrial Biology Group, Department of Physiology, University College London, London WC1E 6BT, United Kingdom
    J Neurosci 24:565-75. 2004
    ....
  45. ncbi Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines
    Jessica Koenigsknecht-Talboo
    Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA
    J Neurosci 25:8240-9. 2005
    ..These findings support anti-inflammatory therapies for the treatment of AD...
  46. ncbi Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models
    Irene H Cheng
    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA
    J Biol Chem 282:23818-28. 2007
    ..Thus, Abeta*56 is a likelier determinant of functional deficits in hAPP mice than fibrillar Abeta deposits. Therapeutic interventions that reduce Abeta fibrils at the cost of augmenting nonfibrillar Abeta assemblies could be harmful...
  47. ncbi Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology
    H Lin
    Neuroscience Research Institute, University of California, Santa Barbara, California 93016, USA
    FASEB J 15:2433-44. 2001
    b>Amyloid beta protein (AbetaP) is the major constituent of senile plaques associated with Alzheimer's disease (AD). However, its mechanistic role in AD pathogenesis is poorly understood...
  48. ncbi GSK-3alpha regulates production of Alzheimer's disease amyloid-beta peptides
    Christopher J Phiel
    Department of Medicine, Division of Hematology Oncology and Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia, Philadelphia 19104 6148, USA
    Nature 423:435-9. 2003
    ....
  49. ncbi Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta
    T Nakagawa
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 403:98-103. 2000
    ..Thus, caspase-12 mediates an ER-specific apoptosis pathway and may contribute to amyloid-beta neurotoxicity...
  50. ncbi The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels
    Zhongcong Xie
    Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129 4404, USA
    Anesthesiology 104:988-94. 2006
    ..inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease-associated amyloid beta protein (Abeta), the principal peptide component of cerebral beta-amyloid deposits.
  51. ncbi Metabolic regulation of brain Abeta by neprilysin
    N Iwata
    Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako shi 351 0198 Japan
    Science 292:1550-2. 2001
    ..Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation...
  52. ncbi Prediction of "aggregation-prone" and "aggregation-susceptible" regions in proteins associated with neurodegenerative diseases
    Amol P Pawar
    Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
    J Mol Biol 350:379-92. 2005
    ....
  53. pmc Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo
    John R Cirrito
    Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
    Neuron 58:42-51. 2008
    ..These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention...
  54. pmc Cross-talk between two cysteine protease families. Activation of caspase-12 by calpain in apoptosis
    T Nakagawa
    Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Cell Biol 150:887-94. 2000
    ..These data suggest a novel apoptotic pathway involving calcium-mediated calpain activation and cross-talks between calpain and caspase families...
  55. ncbi Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial
    S Gilman
    Department of Neurology, University of Michigan, 300 N Ingalls 3D15, Ann Arbor, MI 48109 0489, USA
    Neurology 64:1553-62. 2005
    ..The authors report the results of a phase IIa immunotherapy trial of AN1792(QS-21) in patients with mild to moderate Alzheimer disease (AD) that was interrupted because of meningoencephalitis in 6% of immunized patients...
  56. ncbi The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer's disease
    Marcus A Westerman
    Department of Neurology, Center for Clinical and Molecular Neurobiology, University of Minnesota, Minneapolis, Minnesota 55455, USA
    J Neurosci 22:1858-67. 2002
    ..These studies also provide a methodological framework within which to investigate these Abeta assemblies in vivo...
  57. ncbi Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology
    Stephan Schilling
    Probiodrug AG, Weinbergweg 22, 06120 Halle S, Germany
    Nat Med 14:1106-11. 2008
    ..The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia...
  58. ncbi Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome
    Salvatore Oddo
    Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, CA 92697, USA
    Neuron 43:321-32. 2004
    ..These findings indicate that Abeta immunization may be useful for clearing both hallmark lesions of AD, provided that intervention occurs early in the disease course...
  59. ncbi The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse
    G P Lim
    Departments of Medicine and Neurology, University of California, Los Angeles, Los Angeles, California 90095, USA
    J Neurosci 21:8370-7. 2001
    ..Microgliosis was also suppressed in neuronal layers but not adjacent to plaques. In view of its efficacy and apparent low toxicity, this Indian spice component shows promise for the prevention of Alzheimer's disease...
  60. ncbi Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
    B De Strooper
    Experimental Genetics Group, Flemish Institute for Biotechnology VIB4, Center for Human Genetics, K U Leuven, Belgium
    Nature 391:387-90. 1998
    ..Our results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease...
  61. ncbi Intraneuronal Abeta, non-amyloid aggregates and neurodegeneration in a Drosophila model of Alzheimer's disease
    D C Crowther
    Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust MRC Building, Hills Road, Cambridge CB2 2XY, UK
    Neuroscience 132:123-35. 2005
    ..Moreover it provides a platform to dissect the pathways of neurodegeneration in Alzheimer's disease and to develop novel therapeutic interventions...
  62. ncbi Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies
    M P Lambert
    Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, USA
    J Neurochem 79:595-605. 2001
    ..Analogous immuno-neutralization of oligomers in humans may be a key in AD vaccines...
  63. ncbi Inflammation in Alzheimer disease: driving force, bystander or beneficial response?
    Tony Wyss-Coray
    Geriatric Research, Education and Clinical Center, Veterans Administration Palo Alto Health Care System, 3801 Miranda Avenue, Palo Alto, California 94304, USA
    Nat Med 12:1005-15. 2006
    ..Related factors, on the other hand, elicit beneficial responses and can reduce disease...
  64. ncbi Amyloid beta protein immunotherapy neutralizes Abeta oligomers that disrupt synaptic plasticity in vivo
    Igor Klyubin
    Trinity College Institute of Neuroscience, Department of Pharmacology and Therapeutics, Trinity College, Dublin 2, Ireland
    Nat Med 11:556-61. 2005
    ..forms of experimental disease-modifying treatment for Alzheimer disease is immunization against the amyloid beta protein (Abeta), but how this may prevent cognitive impairment is unclear...
  65. ncbi Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study
    Oskar Hansson
    Clinical Memory Research Unit, Department of Clinical Sciences Malmo, Lund University, Sweden
    Lancet Neurol 5:228-34. 2006
    ..Here, we assess the association between CSF biomarkers and incipient Alzheimer's in patients with mild cognitive impairment (MCI)...
  66. ncbi Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils
    J Gotz
    Division of Psychiatry Research, University of Zurich, August Forel Strasse 1, 8008 Zurich, Switzerland
    Science 293:1491-5. 2001
    ..NFTs were composed of twisted filaments and occurred in 6-month-old mice as early as 18 days after Abeta42 injections. Our data support the hypothesis that Abeta42 fibrils can accelerate NFT formation in vivo...
  67. ncbi Microglial chemotaxis, activation, and phagocytosis of amyloid beta-peptide as linked phenomena in Alzheimer's disease
    J Rogers
    L J Roberts Center for Alzheimer s Research, Sun Health Research Institute, P O Box 1278, 10515 West Santa Fe Drive, Sun City, AZ 85372, USA
    Neurochem Int 39:333-40. 2001
    ..This presents a critical dilemma for strategies to remove A beta by enhancing micoglial activation--a dilemma that warrants substantial further investigation...
  68. pmc Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer's disease mice
    Suzanne E Hickman
    Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, and Division of Infectious Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129
    J Neurosci 28:8354-60. 2008
    ..Antiinflammatory therapy for AD should take this dichotomous microglial role into consideration...
  69. pmc Tau is essential to beta -amyloid-induced neurotoxicity
    Mark Rapoport
    Institute for Neuroscience, Northwestern University, Chicago, IL 60611, USA
    Proc Natl Acad Sci U S A 99:6364-9. 2002
    ..In addition, the analysis of the composition of the cytoskeleton of tau-depleted neurons suggested that the formation of more dynamic microtubules might confer resistance to Abeta-mediated neurodegeneration...
  70. ncbi Microglial activation resulting from CD40-CD40L interaction after beta-amyloid stimulation
    J Tan
    The Roskamp Institute, University of South Florida, 3515 East Fletcher Avenue, Tampa, FL 33613, USA
    Science 286:2352-5. 1999
    ..Finally, abnormal tau phosphorylation was reduced in Tg APPsw animals deficient for CD40L, suggesting that the CD40-CD40L interaction is an early event in AD pathogenesis...
  71. ncbi Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase
    Joanna L Jankowsky
    Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
    Hum Mol Genet 13:159-70. 2004
    ..These data suggest that PS1 variants do not simply alter the preferred cleavage site for gamma-secretase, but rather that they have more complex effects on the regulation of gamma-secretase and its access to substrates...
  72. ncbi Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide
    Christian Haass
    Adolf Butenandt Institute, Department of Biochemistry, Laboratory for Alzheimer s and Parkinson s Disease Research, Ludwig Maximilians University, 80336 Munich, Germany
    Nat Rev Mol Cell Biol 8:101-12. 2007
    ..Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins...
  73. pmc Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism
    Yuequan Shen
    Ben May Institute for Cancer Research, The University of Chicago, 929 East 57th Street, Chicago, Illinois 60637, USA
    Nature 443:870-4. 2006
    ..The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations...
  74. ncbi Role of the toll-like receptor 4 in neuroinflammation in Alzheimer's disease
    Silke Walter
    Department of Neurology, University of the Saarland, Homburg, Germany
    Cell Physiol Biochem 20:947-56. 2007
    ..Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer's disease...
  75. ncbi Neprilysin gene transfer reduces human amyloid pathology in transgenic mice
    Robert A Marr
    Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
    J Neurosci 23:1992-6. 2003
    ..These data further support a role for neprilysin in regulating cerebral amyloid deposition and suggest that gene transfer approaches might have potential for the development of alternative therapies for Alzheimer's disease...
  76. ncbi Monoclonal antibodies that target pathological assemblies of Abeta
    Mary P Lambert
    Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA
    J Neurochem 100:23-35. 2007
    ....
  77. pdf Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry
    Heiko Braak
    Institute for Clinical Neuroanatomy, J W Goethe University Clinic, Theodor Stern Kai 7, 60590 Frankfurt Main, Germany
    Acta Neuropathol 112:389-404. 2006
    ..It is anticipated that this revised methodological protocol will enable a more uniform application of the staging procedure...
  78. ncbi RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain
    Rashid Deane
    Frank P Smith Laboratories for Neurosurgery, Department of Neurosurgery and Division of Neurovascular Biology, Center for Aging and Developmental Biology, University of Rochester Medical Center, Rochester, New York 14642, USA
    Nat Med 9:907-13. 2003
    ..These findings suggest that vascular RAGE is a target for inhibiting pathogenic consequences of Abeta-vascular interactions, including development of cerebral amyloidosis...
  79. ncbi Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease
    A Goate
    Department of Biochemistry, St Mary s Hospital Medical School, London, UK
    Nature 349:704-6. 1991
    ..Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene...
  80. ncbi Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans
    Anne M Fagan
    Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA
    Ann Neurol 59:512-9. 2006
    ..This decrease may reflect plaques acting as an Abeta(42) "sink," hindering transport of soluble Abeta(42) between brain and CSF. We investigated this hypothesis...
  81. ncbi Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders
    Byron Caughey
    NIAID, National Institutes of Health, Rocky Mountain Laboratories, Hamilton, Montana, USA
    Annu Rev Neurosci 26:267-98. 2003
    ..This review focuses on recent experimental studies aimed at identification and characterization of the neurotoxic protein aggregates...
  82. ncbi Longer forms of amyloid beta protein: implications for the mechanism of intramembrane cleavage by gamma-secretase
    Yue Qi-Takahara
    Department of Neuropathology, Faculty of Medicine, University of Tokyo, Tokyo 113 0033, Japan
    J Neurosci 25:436-45. 2005
    Gamma-cleavage of beta-amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid beta protein (Abeta), and epsilon-cleavage, approximately 10 residues downstream of the gamma-cleavage site, releases the APP ..
  83. ncbi Early-onset and robust cerebral microvascular accumulation of amyloid beta-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid beta-protein precursor
    Judianne Davis
    Department of Medicine, Health Sciences Center, Stony Brook University, Stony Brook, NY 11794 8153, USA
    J Biol Chem 279:20296-306. 2004
    ..These results with Tg-SwDI mice demonstrate that overexpression of human AbetaPP is not required for early-onset and robust accumulation of both vascular and parenchymal Abeta in mouse brain...
  84. ncbi Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death
    Malcolm 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...
  85. pmc The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease
    Ekaterina Rogaeva
    Centre for Research in Neurodegenerative Diseases, Department of Medicine, Department, University of Toronto, Toronto, Ontario, Canada
    Nat Genet 39:168-77. 2007
    ..These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease...
  86. ncbi LRP/amyloid beta-peptide interaction mediates differential brain efflux of Abeta isoforms
    Rashid Deane
    Frank P Smith Laboratories for Neuroscience and Neurosurgical Research, Department of Neurosurgery, Arthur Kornberg Medical Research Building, University of Rochester Medical Center, Rochester, NY 14642, USA
    Neuron 43:333-44. 2004
    ..Thus, low-affinity LRP/Abeta interaction and/or Abeta-induced LRP loss at the BBB mediate brain accumulation of neurotoxic Abeta...
  87. ncbi Regulation of NMDA receptor trafficking by amyloid-beta
    Eric M Snyder
    Laboratory for Molecular and Cellular Neuroscience, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
    Nat Neurosci 8:1051-8. 2005
    ..Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology...
  88. ncbi Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer's disease brain contribute to neuronal death
    D Allan Butterfield
    Department of Chemistry, Center of Membrane Sciences, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40506 0055, USA
    Neurobiol Aging 23:655-64. 2002
    ....
  89. ncbi A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease
    G Chen
    Department of Neuroscience, University of Edinburgh, UK
    Nature 408:975-9. 2000
    ....
  90. ncbi 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...
  91. ncbi BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics
    S L Roberds
    Department of Genomics, Pharmacia Corp, 301 Henrietta Street, Kalamazoo, MI 49007, USA
    Hum Mol Genet 10:1317-24. 2001
    ....
  92. pmc Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo
    Wesley Farris
    Center for Neurologic Diseases, Department of Neurology, Brigham and Women s Hospital, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 100:4162-7. 2003
    ....
  93. ncbi Identification and characterization of key kinetic intermediates in amyloid beta-protein fibrillogenesis
    M D Kirkitadze
    Center for Neurologic Diseases, Brigham and Women s Hospital, Boston, MA 02115, USA
    J Mol Biol 312:1103-19. 2001
    ..These data emphasize the importance of the dynamic interplay between Abeta monomer conformation and oligomerization state in controlling fibrillogenesis kinetics...
  94. ncbi Acute impairment of mitochondrial trafficking by beta-amyloid peptides in hippocampal neurons
    Yanfang Rui
    Department of Biological Science and Biotechnology, State Key Laboratory of Biomembrane and Membrane Biotechnology, Tsinghua University, Beijing, China 100084
    J Neurosci 26:10480-7. 2006
    ..Manipulation of GSK3beta and PKA activities may represent a key approach for preventing and alleviating Abeta cytotoxicity and AD pathological conditions...
  95. ncbi Passive amyloid immunotherapy clears amyloid and transiently activates microglia in a transgenic mouse model of amyloid deposition
    Donna M Wilcock
    Alzheimer s Research Laboratory, University of South Florida, Tampa, Florida 33612, USA
    J Neurosci 24:6144-51. 2004
    ..Together with our earlier work, our data argue that all proposed mechanisms of anti-Abeta antibody-mediated amyloid removal can be simultaneously active...
  96. ncbi The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice
    Sabine Ring
    Department of Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, University of Heidelberg, D 69120 Heidelberg, Germany
    J Neurosci 27:7817-26. 2007
    ..Together, our data suggest that the APP C terminus is dispensable and that APPs alpha is sufficient to mediate the physiological functions of APP assessed by these tests...
  97. ncbi TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity
    Fusheng Chen
    Department of Medicine, and Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 3H2
    Nature 440:1208-12. 2006
    ..Here we report that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage without affecting epsilon-secretase activity...
  98. ncbi The human DIMINUTO/DWARF1 homolog seladin-1 confers resistance to Alzheimer's disease-associated neurodegeneration and oxidative stress
    I Greeve
    Center for Molecular Neurobiology Hamburg, University of Hamburg, 20246 Hamburg, Germany
    J Neurosci 20:7345-52. 2000
    ..Decreased expression of seladin-1 in specific neurons may be a cause for selective vulnerability in AD...
  99. ncbi High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation
    L Mucke
    Gladstone Institute of Neurological Disease, Department of Neurology, and Neuroscience Program, University of California, San Francisco, California 94141 9100, USA
    J Neurosci 20:4050-8. 2000
    ..Our results support the emerging view that plaque-independent Abeta toxicity plays an important role in the development of synaptic deficits in AD and related conditions...
  100. ncbi In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life
    John R Cirrito
    Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Neurosci 23:8844-53. 2003
    ..This now measurable in vivo pool is a likely target for new diagnostic and therapeutic strategies...
  101. ncbi PET imaging of amyloid deposition in patients with mild cognitive impairment
    Anton Forsberg
    Karolinska Institute, Department of Neurobiology, Care Sciences and Society, Stockholm, Sweden
    Neurobiol Aging 29:1456-65. 2008
    ..01). The PIB retention in MCI converters was comparable to AD patients (p>0.01). Correlations were observed in the MCI patients between PIB retention and CSF Abeta(1-42), total Tau and episodic memory, respectively...

Research Grants65

  1. Amyloid Beta-Protein: ApoE and Cholesterol Homeostasis
    WELLINGTON WOOD; Fiscal Year: 2009
    ..Determine if the neuronal apoE4 and apoE-null phenotype can be "rescued" by incubation with astrocytes of apoE2, apoE3, or wildtype mice. In some experiments astrocytes will be treated with ABeta1-42. ..
  2. Antisense Oligonucleotide Treatment for Alzheimer's Disease
    Susan A Farr; Fiscal Year: 2013
    ..Learning and memory deficits are the hallmark of Alzheimer's disease and amyloid beta protein (A[unreadable]) plays a key role in these deficits...
  3. Structural Biology of Amyloid Beta-Protein
    David B Teplow; Fiscal Year: 2013
    ..The project also will be of relevance to Parkinsons, Huntingtons, amyotrophic lateral sclerosis, familial amyloid polyneuropathy, the prionoses, and other neurodegenerative diseases of aging. ..
  4. A noninvasive optical imaging of retinal amyloid beta deposits in AD patients
    Maya Koronyo-Hamaoui; Fiscal Year: 2013
    ..With the current limitations in obtaining a definitive and early diagnostic test for AD, the commercial implications of the proposed study have the potential to make a significant impact on the market. ..
  5. Synaptic dysregulation in a mouse model of Alzheimer's disease
    Daniel A Nicholson; Fiscal Year: 2011
    ..microscopy and whole-cell patch-clamp physiology in transgenic mice that overproduce toxic species of the amyloid beta protein and their non-transgenic littermate controls to identify which synapses are most sensitive to AD-like ..
  6. Pathologic protein folding and human disease
    David B Teplow; Fiscal Year: 2010
    ..We thus envision the significance of the Program extending beyond solely AD. ..
  7. Protein-Protein Interactions in the Biology of Beta-APP
    Dennis J Selkoe; Fiscal Year: 2012
    ..We will also explore new ways to increase the cutting up or the transport of Abeta as future therapeutic approaches for preventing Alzheimer's disease. ..
  8. Physical Biochemistry and Biology of Amyloid Beta-Protein
    David B Teplow; Fiscal Year: 2013
    ..Aim 3. To identify and validate AD-relevant genes using a bioinformatics approach that considers A? assembly structure, neuron type, and neuron senescence. ..
  9. LRP/RanBP9 Pathway in Alzheiimer's Disease Pathogenesis
    David E Kang; Fiscal Year: 2011
    ..career are to 1) clearly understand the molecular and cellular mechanisms that drive the accumulation of amyloid beta protein in Alzheimer's disease, 2) mechanistically define signaling pathways that mediate and/or potentiate ..
  10. Synaptic damage in models of beta-amyloid associated pathology
    Edward H Koo; Fiscal Year: 2011
    ..Axons in the latter mutant animals are protected in injury and from various toxic agents and neurodegeneration. Consequently, we can test whether preserving axons can attenuate synaptic damage in APP transgenic mice. ..
  11. Presenilin Biology and the Mechanisms of Alzheimer's Disease
    RUDOLPH EMILE TANZI; Fiscal Year: 2013
    ..In short, we are committed to applying novel approaches to elucidate the structure and function of gamma-secretase in health and disease. ..
  12. Gamma-Secretase: Structure of an Intramembrane Protease
    Huilin Li; Fiscal Year: 2013
    ..This work should yield far more structural and mechanistic information on the unusual intramembrane enzyme, which is required for cell-fate decisions in all metazoans. ..
  13. Understanding the Neuroprotective Activities of Posiphen
    Kumar Sambamurti; Fiscal Year: 2013
    ..Transgenic mice expressing Amyloid beta protein (A[unreadable]) precursor (APP) deposit amyloid but do not present degeneration phenotypes...
  14. Pathologic Interactions of Amyloid Beta-Protein
    William E Van Nostrand; Fiscal Year: 2011
    ..We will utilize a combination of biochemical, molecular, ultrastructural, and cell culture approaches to understand these interactions and the consequences of them. ..
  15. CEREBROVASCULAR AMYLOIDOSIS
    Peter Gorevic; Fiscal Year: 1999
    ..the prion diseases, certain hereditary stroke-like syndromes due to cystatin C or Alzheimer's disease (AD) amyloid beta protein (Ab) deposition, and Ab deposition in AD and related disorders...
  16. ROLES OF VASCULAR AMYLOID BETA PROTEIN PRECURSOR
    William Van Nostrand; Fiscal Year: 1999
    ..Better understanding of the biochemistry and cerebrovascular cell biology of PN- 2/AbetaPP will provide insight into its normal function as well as the patho-biochemistry and pathophysiology of this protein in certain disease states. ..
  17. INHIBITION OF AMYLOID FORMATION BY TRANSTHYRETIN & APOE
    Dmitry Goldgaber; Fiscal Year: 1999
    ..b>Amyloid beta protein (Ab) is the principal component of poorly soluble extracellular amyloid depositions found in the brains and ..
  18. TRISOMY 16 AND NGF--EFFECTS ON CNS GENE EXPRESSION
    David Holtzman; Fiscal Year: 1993
    Several neuronal genes expressed in the CNS, including the amyloid beta protein precursor (APP) have been assigned to human chromosome 21 (HSA 21)...
  19. Acquiring robotic support for mass spectrometry core
    CRAIG MALBON; Fiscal Year: 2003
    ..The institution has provided resources to enable the acquisition of two new mass spectrometers and this proposal builds on the investment. ..
  20. PATHOLOGY IN ALZHEIMER'S DISEASE
    Gerald Higgins; Fiscal Year: 1990
    ..Subsequent studies will be undertaken in human brain, to determine if a similar relationship exists between nerve growth factor receptor regulation and hippocampal pathology and gene expression in AD...
  21. Alzheimer Vaccines: Noninvasive Vaccination by DNA-Base*
    Ken Ichiro Fukuchi; Fiscal Year: 2005
    ..The nasal membrane application procedure eliminates pain and other problems associated with needle injection, protein purification, and adjuvant modification, and so may reduce medical costs. ..
  22. Structure determination by vibrational spectroscopy
    Paul H Axelsen; Fiscal Year: 2013
    ..and molecular mechanics simulation to answer key questions about the formation and structure of amyloid beta protein fibrils. There are two specific aims: 1. Correlate structure and morphology in amyloid fibrils. 2...
  23. BIOCHEMISTRY AND BIOPHYSICS OF BPTI FOLDING MUTANTS
    Stephen Anderson; Fiscal Year: 1993
    ..the lipoprotein-associated coagulation inhibitor and the alternatively-spliced domain of the Alzheimer's amyloid beta protein precursor...
  24. REGULATION OF AMYLOID BETA PROTEIN BY APOE & CHOLESTEROL
    Bruce Yankner; Fiscal Year: 2004
    ..These studies may help to elucidate the roles of apoE and dietary cholesterol in the pathogenesis of AD, with potentially important implications for early genotyping and therapeutic intervention. ..
  25. PNA'S AS MODULATORS OF PRESENILIN EXPRESSION
    Todd Golde; Fiscal Year: 2000
    ..the mouse presenilin 1 (PS1) gene reduce presenilin expression and lead to alterations in production of the amyloid beta protein (Abeta) both in vitro and in vivo...
  26. Antibodies Against Amyloid Beta-Protein Intermediates
    ROBERT LAWTON; Fiscal Year: 2003
    ..Generation and initial characterization of these antibodies in this phase will be the foundation for further in vitro and in vivo characterization in Phase II, as well as the scale-up of the antibody production. ..
  27. The Role of Sortilin in Alzheimer's Disease
    GINA FINAN; Fiscal Year: 2009
    ..This is to be accomplished through a variety of techniques, some including: immunofluorescence, subcellular fractionation, RNAi, Western blot, and ELISA. ..
  28. APP INTERNALIZATION--PREREQUISITE FOR ABETA FORMATION?
    Edward Koo; Fiscal Year: 2000
    ..Results from these studies should provide significant insights into the relationship between APP internalization, APP proteolysis, ABeta release, and familial Alzheimer's disease mutations. ..
  29. MELATONIN- A NEW ANTI-AMYLOIDOGENIC & ANTIOXIDANT AGENT
    Miguel Pappolla; Fiscal Year: 2003
    ..in sporadic Alzheimer's disease (AD) is a result, at least in part, of the neurotoxic properties of the amyloid beta protein (Abeta). Deposits of this protein are widespread within the brains of individuals affected with AD...
  30. PATHOLOGY OF BRAIN METABOLISM IN ALZHEIMERS DISEASE
    Michael Mega; Fiscal Year: 2001
    ..b>Amyloid beta protein (ABeta) may contribute to the pathophysiology of AD-the mechanism may involve oxidative damage contributing ..
  31. FUNCTION OF AN APP CYTOPLASMIC DOMAIN BINDING PROTEIN
    I Shapiro; Fiscal Year: 1999
    ..These studies will investigate a novel finding and a new aspect of the regulation of APP processing and should have a direct impact on understanding APP processing and possibly AD pathogenesis. ..
  32. p75NTR proteolysis in Alzheimer's Disease
    Natalie Landman; Fiscal Year: 2006
    ..Specific Aims are: 1) To examine the functional roles of p75-beta-p and p75-ICD fragments; 2) To determine the effects of PS mutations on proteolysis/signaling of the p75NTR. ..
  33. TRANSGENIC MODELS OF ALZHEIMERS DISEASE
    Michael Irizarry; Fiscal Year: 2001
    ..Genetic, cell culture, and animal studies support a key role of the amyloid precursor protein (APP) and amyloid beta protein (alpha beta) in the pathogenesis of AD, and related disorder, congophilic amyloid angiopathy (CAA)...
  34. Identify Abeta Oligomer Inhibitors By Combinatorial Chemistry
    Lee Way Jin; Fiscal Year: 2009
    ..These compounds can be developed into therapeutic agents for Alzheimer's disease or into imaging agents for radiological diagnosis of Alzheimer's disease, a leading cause of dementia worldwide. ..
  35. Amyloid Beta-Protein: Wild Type and Familial Mutant Assembly and Inhibition
    MICHAEL THOMAS BOWERS; Fiscal Year: 2013
    ..No abstract provided ..
  36. Molecular Modeling of Amyloid-beta Oligomer Formation
    H Eugene Stanley; Fiscal Year: 2006
    ..Predictions emanating from these analyses then will be tested experimentally in Dr. Teplow's laboratory through chemical synthesis of appropriate ABeta peptides and study of their assembly and neurotoxic activity. ..
  37. Effects of apoE on Abeta Structure and Neuritic Toxicity
    ROBERT BRENDZA; Fiscal Year: 2003
    ..abstract_text> ..
  38. PRESENILINS, APOPTOSIS AND AMYLOID BETA PROTEIN
    Joseph Buxbaum; Fiscal Year: 2003
    ..abstract_text> ..
  39. Interaction of amyloid-beta protein with lipid membranes
    EVA CHI; Fiscal Year: 2006
    ..The link between amyloid-beta-membrane interactions and neurotoxicity will be evaluated ..
  40. Prion Transport Across the Blood-Brain Barrier
    William Banks; Fiscal Year: 2009
    ..To cause disease, prions must cross the blood-brain barrier to enter the brain. We will determine how prions cross the BBB. Knowing how prions enter the brain should lead to strategies on how to prevent prion diseases. ..
  41. Mechanisms of HIV Transport Across the BBB
    William Banks; Fiscal Year: 2004
    ....
  42. Structure and mechanism of signal peptide peptidase
    Michael S Wolfe; Fiscal Year: 2010
    ..A structure of SPP would provide tremendous insight into the workings of an unusual new class of enzymes that are critical to both biology and medicine. ..
  43. PTS1 Regulation of Brain Met Enk Levels in Alcoholism
    William Banks; Fiscal Year: 2004
    ..abstract_text> ..
  44. The Role of Presenilin in Gamma-Secretase Activity
    Michael Wolfe; Fiscal Year: 2009
    ..for substrate-protease recognition? (3) What is the role of Aph-1 and NCT in the assembly and activity of the protease complex? (4) How do mutations in PS that cause familial AD alter the specificity and activity of gamma-secretase? ..
  45. Opiate Addiction and HIV-1 Induced Release of Cytokines
    William Banks; Fiscal Year: 2006
    ....
  46. PRESENILIN ENDOPROTEASE & GAMMA-SECRETASE ACTIVITY
    Weiming Xia; Fiscal Year: 2003
    ..abstract_text> ..
  47. EFFECTS OF AGING & PGP ON AB EFFLUX FROM THE BRAIN
    ANNE FAGAN NIVEN; Fiscal Year: 2005
    ..Support for the hypothesis would establish a role for age-dependent defects in A-beta clearance from the brain in the pathogenesis of AD and, importantly, provide a novel therapeutic target for treatment of the disease. ..
  48. BETA AND ITS PRECURSOR INFLUENCE HEMOSTATIC ENZYMES
    William Van Nostrand; Fiscal Year: 2001
    ....
  49. INTEGRATED DNA SEQUENCING SYSTEM
    Vivian Hook; Fiscal Year: 2002
    ..abstract_text> ..
  50. PET IMAGING PROBES FOR AMYLOID IN ALZHEIMERS AND AGING
    William Klunk; Fiscal Year: 2005
    ....
  51. PET TRACERS TO MONITOR VACCINE AND IMMUNE THERAPY FOR AD
    William Klunk; Fiscal Year: 2005
    ....
  52. Proteomics/Genomics of Opiate Analgesia and Addiction
    Vivian Hook; Fiscal Year: 2004
    ..Elucidation of distinct pathways will be significant, since it could allow future design of opiate drug regimens that provide effective analgesia, without the tolerance and dependence of addiction. ..
  53. AbetaPP and Cerebral Vasculopathy
    William Van Nostrand; Fiscal Year: 2006
    ..unreadable] [unreadable]..
  54. A screen for small molecule inhibitors of soluble Abeta oligomer assembly
    Harry LeVine; Fiscal Year: 2007
    ..Anti-oligomer compounds could potentially block the cognitive impairment symptoms that oligomers elicit in animal models and interfere with the progression of Alzheimer's disease. [unreadable] [unreadable] [unreadable]..
  55. Molecular and Functional Imaging of Age Related Cognitive Decline
    William Jagust; Fiscal Year: 2009
    ....
  56. Alpha-Synuclein, PUFA and Membrane Vesicles in Health and Parkinson's Disease
    Dennis J Selkoe; Fiscal Year: 2010
    ..New findings emanating from this grant should simultaneously shed light on the physiology of aS and the earliest steps in its pathological oligomerization, with attendant therapeutic insights. ..
  57. Cerebral Microvascular Amyloid: Neuroinflammation and Cognitive Deficits
    William E Van Nostrand; Fiscal Year: 2010
    ....
  58. Amyloid Beta Protein Precursor Influences Cerebral Thrombosis
    William E Van Nostrand; Fiscal Year: 2010
    ..This may lead to new avenues for developing strategies to regulate cerebral thrombosis and limit damage to the brain as a consequence of hemorrhagic and ischemic stroke. ..
  59. POMC Processing and Beta-Endorphine-Related Opioid Peptides
    Vivian Y H Hook; Fiscal Year: 2010
    ..New findings from this project will enhance our knowledge of the complexity of biosynthetic mechanisms for endogenous opioid and neuropeptide systems. ..
  60. BIOSYNTHESIS OF ENKEPHALIN OPIOID PEPTIDES
    Vivian Hook; Fiscal Year: 2009
    ..These findings will enhance our knowledge of the complexity of the endogenous opioid system. ..
  61. Transgenic Model for Cerebral Amyloid Angiopathy
    William Van Nostrand; Fiscal Year: 2006
    ..unreadable] [unreadable]..
  62. Serpin Protease Inhibitors & Opioid Neuropeptides
    Vivian Hook; Fiscal Year: 2006
    ..Serpin regulation of opioid peptides that mediate analgesia and stress may lead to development of new therapeutic approaches in pain and neurologic disease. ..
  63. Effects of Chemotherapy on Brain Function
    William J Jagust; Fiscal Year: 2010
    ..They are also relevant to the overall mission of the NIH because of the negative impact that cognitive dysfunction has on quality of life. ..
  64. Gene Expression in Alzheimer's Disease
    Walter Lukiw; Fiscal Year: 2006
    ..abstract_text> ..