Toxic Protofibrillar Aβ

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

Comments

    • User Profile Image David Teplow
      David Geffen School of Medicine at UCLA
    • Posted:

    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.

    References:

    Walsh DM, Hartley DM, Kusumoto Y, Fezoui Y, Condron MM, Lomakin A, Benedek GB, Selkoe DJ, Teplow DB. Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates. J Biol Chem. 1999 Sep 3;274(36):25945-52. PubMed.

    View all comments by David Teplow

  2. 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 Koudinov

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Further Reading

Papers

  1. Nelson PT, Keller JN. RNA in brain disease: no longer just "the messenger in the middle". J Neuropathol Exp Neurol. 2007 Jun;66(6):461-8. PubMed.
  2. Wang WX, Rajeev BW, Stromberg AJ, Ren N, Tang G, Huang Q, Rigoutsos I, Nelson PT. The expression of microRNA miR-107 decreases early in Alzheimer's disease and may accelerate disease progression through regulation of beta-site amyloid precursor protein-cleaving enzyme 1. J Neurosci. 2008 Jan 30;28(5):1213-23. PubMed.

Primary Papers

  1. Hartley DM, Walsh DM, Ye CP, Diehl T, Vasquez S, Vassilev PM, Teplow DB, Selkoe DJ. 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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