. The extracellular chaperone clusterin sequesters oligomeric forms of the amyloid-β(1-40) peptide. Nat Struct Mol Biol. 2012 Jan;19(1):79-83. PubMed.

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  1. This paper by Narayan et al. beautifully illustrates that purified human clusterin interacts in vitro with in-vitro prepared Aβ and inhibits oligomer and fibril formation, and that clusterin also directly interacts with Aβ oligomers. In binding pre-formed oligomers, clusterin halted further Aβ self-association and decreased oligomer concentration in solution. One might predict from these findings, as the authors did in their discussion, that human clusterin is protective against Aβ oligomer formation and toxicity. They state that "the ability of clusterin to sequester misfolded and potentially toxic oligomers provides a molecular basis for the recently identified genetic association between clusterin and Alzheimer's disease. Indeed, any perturbations that result in reduced clusterin levels, or in a reduction in the ability of clusterin to form stable and long-lived complexes with Aβ oligomers, are likely to increase susceptibility to Alzheimer's disease." I would agree with the authors’ conclusions based on these in-vitro studies.

    However, our group previously assessed the effects of crossing mice that develop Aβ aggregation in the brain (PDAPP mice) with mice that either express or lack murine clusterin (DeMattos et al., 2002 and ARF related news story). In that paper, we showed that the absence of clusterin significantly decreased true Aβ fibril formation as well as markedly reduced neuritic damage around the Aβ aggregates that did form. Thus, the in-vivo data show that, at least in regard to Aβ, clusterin promotes fibril formation and toxicity. In some ways, this is the opposite prediction of the work by Narayan et al. One cannot do the type of beautiful assessment of oligomers in vivo as was done in the Narayan paper, so we do not know what the status of oligomers was in the presence or absence of clusterin in vivo. It is possible that mouse and human clusterin would have different effects in vivo which could account for what could be interpreted as a discrepancy between the in-vivo and in-vitro data. Alternatively, assessing the effects of two purified proteins in vitro may not be able to mimic the more complex milieu present in vivo. Further studies will be required to sort out whether human clusterin is actually promoting or inhibiting toxic forms of Aβ in vivo.

    References:

    . Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2002 Aug 6;99(16):10843-8. PubMed.