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Neurodegenerative diseases

Clearing up Aβ

Nature Reviews Drug Discovery volume 7, page 645 (2008)Cite this article

In the first paper, published in Proceedings of the National Academy of Sciences, Jacobsen and colleagues investigated the role of plasmin — a protease that is generated from the cleavage of plasminogen by tissue plasminogen activator (tPA) — in the breakdown of Aβ. By screening a compound library, the authors identified PAZ-417 as a potent and selective inhibitor of plasminogen activator inhibitor-1 (PAI-1), a known inhibitor of the plasmin cascade.

In vitro assays revealed that PAZ-417 augmented tPA, which led to plasmin generation and induced the cleavage of synthetic monomeric and oligomeric Aβ. In a transgenic mouse model of Alzheimer's disease, PAI-1 inhibition led to a twofold increase in hippocampal tPA activity. Next, clearance of plasma and brain Aβ was measured in two mouse models (plaque- and non-plaque-bearing ages), in which a single oral dose of PAZ-417 resulted in reduced plasma and brain Aβ levels in both mouse types.

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ORIGINAL RESEARCH PAPERS

  1. Jacobsen, J. S. et al. Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade. Proc. Natl Acad. Sci. USA 105, 8754–8759 (2008)

    Article  CAS  Google Scholar 

  2. Jiang, Q. et al. ApoE promotes the proteolytic degradation of Aβ. Neuron 58, 681–693 (2008)

    Article  CAS  Google Scholar 

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Authors
  1. Charlotte Harrison
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Harrison, C. Clearing up Aβ. Nat Rev Drug Discov 7, 645 (2008). https://doi.org/10.1038/nrd2644

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  • DOI: https://doi.org/10.1038/nrd2644

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