Diffusible, nonfibrillar ligands derived from Aβ 1–42 are potent central nervous system neurotoxins

Proceedings of the National Academy of Sciences of the United States of America - Tập 95 Số 11 - Trang 6448-6453 - 1998
Mary P. Lambert1, Avlin K. Barlow1, Brett A. Chromy1, Cathryn Edwards1, Rachel D. Freed1, M. Liosatos1, Todd E. Morgan1, Irina Rozovsky1, Barbara L. Trommer1, Kirsten L. Viola1, P.A. Wals1, C. Zhang1, Caleb E. Finch1, Grant A. Krafft1, William L. Klein1
1Department 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

Tóm tắt

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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 95 Số 11

6448-6453

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