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The Journal of Neuroscience, October 15, 1999, 19(20):8876-8884
Protofibrillar Intermediates of Amyloid  -Protein Induce Acute
Electrophysiological Changes and Progressive Neurotoxicity in Cortical
Neurons
Dean M.
Hartley2,
Dominic M.
Walsh2,
Chianping P.
Ye1, 3,
Thekla
Diehl2,
Sara
Vasquez2,
Peter M.
Vassilev1, 3,
David B.
Teplow2, and
Dennis. J.
Selkoe2
1 Department of Neurology and Medicine,
Harvard Medical School, and the 2 Center for
Neurologic Diseases and 3 Division of
Endocrinology, Department of Medicine, Brigham and Women's Hospital,
Boston, Massachusetts 02115
Alzheimer's disease (AD) is a progressive neurodegenerative
disorder that is thought to be caused in part by the age-related accumulation of amyloid  -protein (A). The presence of neuritic plaques containing abundant A-derived amyloid fibrils in AD brain tissue supports the concept that fibril accumulation per se underlies neuronal dysfunction in AD. Recent observations have begun to challenge
this assumption by suggesting that earlier A assemblies formed
during the process of fibrillogenesis may also play a role in AD
pathogenesis. Here, we present the novel finding that protofibrils (PF), metastable intermediates in amyloid fibril formation, can alter
the electrical activity of neurons and cause neuronal loss. Both low
molecular weight A (LMW A) and PF reproducibly induced toxicity
in mixed brain cultures in a time- and concentration-dependent manner.
No increase in fibril formation during the course of the experiments
was observed by either Congo red binding or electron microscopy,
suggesting that the neurotoxicity of LMW A and PF cannot be
explained by conversion to fibrils. Importantly, protofibrils, but not
LMW A, produced a rapid increase in EPSPs, action potentials, and membrane depolarizations. These data suggest that PF have inherent
biological activity similar to that of mature fibrils. Our results
raise the possibility that the preclinical and early clinical
progression of AD is driven in part by the accumulation of specific
A assembly intermediates formed during the process of fibrillogenesis.
Key words:
Alzheimer; amyloid -protein; neurotoxicity; electrophysiology; fibrillogenesis; neurodegeneration
Copyright © 1999 Society for Neuroscience 0270-6474/99/19208876-09$05.00/0
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D. J. Selkoe
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D. L. Rymer and T. A. Good
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