Diffusible, nonfibrillar ligands derived from Aβ _1–42 are potent central nervous system neurotoxins

• M. P. Lambert

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• A. K. Barlow

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• B. A. Chromy

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• C. Edwards

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• R. Freed

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• M. Liosatos

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• T. E. Morgan

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• I. Rozovsky

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• B. Trommer

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• K. L. Viola

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• P. Wals

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• C. Zhang

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• C. E. Finch

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• G. A. Krafft

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

• W. L. Klein

  Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208; Evanston Hospital Research Division, Evanston, IL, 60201; Pediatrics and Neurology, Evanston Hospital, Evanston, IL, 60201; Andrus Gerontology Center, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089; Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201; and Department of Neurology,Northwestern University Medical School, Chicago, IL 60611

抄録

Aβ 1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Aβ oligomers (referred to as ADDLs, for Aβ-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis and elevated in Alzheimer’s disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer’s disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Aβ-derived diffusible ligands acting upon particular neural signal transduction pathways.

収録刊行物

• Proceedings of the National Academy of Sciences

  Proceedings of the National Academy of Sciences 95 (11), 6448-6453, 1998-05-26

  Proceedings of the National Academy of Sciences

キーワード

• Multidisciplinary

詳細情報

• CRID: 1363388845843910400
• NII論文ID: 80010408301
• DOI: 10.1073/pnas.95.11.6448
• ISSN: 10916490
• ISSN: 00278424
• Web Site: https://pnas.org/doi/pdf/10.1073/pnas.95.11.6448
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