From today's Journal of Neuroscience comes evidence that intermediate Aβ species could be damaging neurons. Dean Hartley, Dennis Selkoe, and their colleagues report that so-called "protofibrillar" Aβ (oligomers intermediate between Aβ monomers and amyloid fibrils) can induce electrophysiological changes and progressive toxicity in cortical neurons.

In mixed (neuronal and glial) cultures from embryonic rat neocortex, the addition of either low-molecular-weight (mainly monomeric) Aβ or protofibrils induced toxicity in a time- and concentration-dependent manner, despite the fact that there was no detectable formation of mature amyloid fibrils during this time. Protofibrils, but not low-molecular-weight Aβ, also induced electrophysiological changes (increased EPSPs, action potentials, and membrane depolarizations) in cultured neurons.

Based on this evidence that protofibrils have biologic, and toxic, activity, the authors suggest the possibility that "the preclinical and early clinical progression of AD is driven in part by the accumulation of specific Aβ assembly intermediates...." The role of protofibrillar Aβ in human Alzheimer disease pathogenesis remains to be determined.-Hakon Heimer.

Reference:
Hartley DM, Walsh DM, Chianping PY, et al. Protofibrillar intermediates of amyloid-β protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci 1999;19(20). Abstract

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  1. In the news article cited above, two important facts need
    clarification. First, protofibrils are fibrillar. Second, the first
    demonstration that protofibrils were neurotoxic was published by my
    group, in collaboration with Drs. Hartley, Selkoe, and others, in Walsh
    et al. J Biol Chem on Sept 3 (v274:25945-25952). Abstract

Comments on Primary Papers for this Article

  1. Please see the following letters in Science and BMJ related to this article: Alzheimer's disease and amyloid beta protein Koudinov AR et al Science online,> Published 25 June 2002 [ Full Text ] Amyloid hypothesis, synaptic function, and Alzheimer’s disease, or: Beware: the dogma is revitalized. Koudinov and Koudinova BMJ 15 May 2002 [ Full Text ]

    View all comments by Alexei R. Koudinov

References

Paper Citations

  1. . Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999 Oct 15;19(20):8876-84. PubMed.

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Papers

  1. . Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999 Oct 15;19(20):8876-84. PubMed.
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Primary Papers

  1. . Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J Neurosci. 1999 Oct 15;19(20):8876-84. PubMed.