. 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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  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.

  2. 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.

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