Jacobsen JS, Comery TA, Martone RL, Elokdah H, Crandall DL, Oganesian A, Aschmies S, Kirksey Y, Gonzales C, Xu J, Zhou H, Atchison K, Wagner E, Zaleska MM, Das I, Arias RL, Bard J, Riddell D, Gardell SJ, Abou-Gharbia M, Robichaud A, Magolda R, Vlasuk GP, Bjornsson T, Reinhart PH, Pangalos MN. Enhanced clearance of Abeta in brain by sustaining the plasmin proteolysis cascade. Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8754-9. PubMed.

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Comments

  1. This is a truly exciting study that takes advantage of an Aβ-degrading enzyme to increase Aβ turnover. It is particularly useful as this enzyme can clip the oligomers. It will be very useful to know whether the treatment reduces pro-NGF and increases NGF to also provide neurotrophic support, as pro-NGF can be cleaved by plasmin to its mature form.

    View all comments by Kumar Sambamurti

  2. I have not yet read the full paper in PNAS (awaiting requested PDF), but it is extremely pleasing to find that plasmin is still very much on the AD agenda. We were the first to demonstrate that plasmin cleaves Aβ42 (1) and subsequently to show that its activity was inhibited by aluminum (2). While it would appear that the focus of the current study is on AD therapy, one might assume that it will also inform the discussion concerning AD etiology.

    I congratulate this group on their research and await in anticipation the opportunity to read the full paper.

    References:

    Exley C, Korchazhkina OV. Plasmin cleaves Abeta42 in vitro and prevents its aggregation into beta-pleated sheet structures. Neuroreport. 2001 Sep 17;12(13):2967-70. PubMed.

    Korchazhkina OV, Ashcroft AE, Kiss T, Exley C. The degradation of Abeta(25-35) by the serine protease plasmin is inhibited by aluminium. J Alzheimers Dis. 2002 Oct;4(5):357-67. PubMed.

    View all comments by Chris Exley

  3. The Aβ lowering in vivo activity may be due to the very high structural analogy of PAZ-417 to indomethacin and thus γ-secretase modulation.

    The additional phenyl group is tolerated by γ-secretase (see flurbiprofen). Therefore, the observed effect (at the applied concentrations) may in fact be due to γ-secretase inhibition or modulation and not the plasmin cascade. Alternatively, some γ-secretase modulators may operate through the plasmin cascade.

    A reconstituted γ-secretase assay could answer the pending questions.

    View all comments by Boris Schmidt

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