. Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity. J Neurosci. 2008 Nov 12;28(46):11950-8. PubMed.

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  1. The paper by Hung et al. adds interesting new aspects to the prevalent hypothesis that Aβ peptides are the main trigger for the neuronal degeneration characteristics of Alzheimer disease (AD) (Hardy and Selkoe, 2002). As previously shown by us (Munter et al., 2007), Aβ42 generation presumably depends on the dimerization of the α-helical APP transmembrane sequence mediated by a GxxxG motif encompassing Aβ residues G29 and G33. Kukar et al. then went further and reported that this motif embedded in the plasma membrane is targeted by γ-secretase modulators (GSMs) reducing Aβ42 levels (Kukar et al., 2008).

    The excitement of the present work comes from the finding that GSL peptides, so called because glycine residues were substituted for leucine residues within the GxxxG interaction motif of the Aβ sequence, can directly influence the viability of cortical neurons and, most importantly, binding of Aβ oligomers to lipids. Firstly, to understand the main message of this paper by Hung et al., one needs to point out that the GxxxG motif has a second role with a major impact on Aβ aggregation, as was initially shown by others in vitro (Sato et al., 2006). By using the MTS reduction assay the authors identified amino acid residues G33 and G37 as the major players in mediating toxicity, as leucine substitutions of these residues were non-toxic, whereas effects of G25 and G29 exchanges to leucines were less pronounced.

    The fibril formation profile as measured by ThT and EM differed the most from wild-type for the same two residues, G33 and G37. These rather biophysically oriented data are leading the reader of this paper to its actual highlights. The authors extended the SELDI-TOF mass spectrometry method to show that 1) oligomeric Aβ species up to tetramers can be unambiguously detected by mass spec using a novel method published elsewhere (Giannakis et al., 2008), and 2) H50 ProteinChip arrays coated with liposomes forming a lipid monolayer can be used to analyze Aβ oligomer binding to the lipid surface.

    Finally, the authors used Annexin V, which is known as a specific inhibitor of oligomer binding to membranes, to show by mass spec that Aβ dimers and trimers bound to lipid in a different manner than did monomers. This opens up a new avenue to prove the not yet commonly accepted hypothesis that "Aβ peptides" impair synaptic function and morphology and initiate the process of neuronal degeneration. The data all point to a fusogenic activity of the Aβ peptide, which may contribute to cytotoxicity by destabilizing the cell membrane.

    However, the central question now is if the molecular link between cellular toxicity, Aβ oligomerization, and inhibition of long-term potentiation (LTP) really exists, in vitro and in vivo, which best would be analyzed in a model system. This would add much more weight to support the hypothesis that Aβ oligomer-induced toxicity is the "initial insult" in AD.

    References:

    . The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002 Jul 19;297(5580):353-6. PubMed.

    . GxxxG motifs within the amyloid precursor protein transmembrane sequence are critical for the etiology of Abeta42. EMBO J. 2007 Mar 21;26(6):1702-12. PubMed.

    . Substrate-targeting gamma-secretase modulators. Nature. 2008 Jun 12;453(7197):925-9. PubMed.

    . Structure of the catalytic pore of gamma-secretase probed by the accessibility of substituted cysteines. J Neurosci. 2006 Nov 15;26(46):12081-8. PubMed.

    . Dimeric structures of alpha-synuclein bind preferentially to lipid membranes. Biochim Biophys Acta. 2008 Apr;1778(4):1112-9. PubMed.

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