. Amyloid-beta neurotoxicity is mediated by FISH adapter protein and ADAM12 metalloprotease activity. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):3058-63. PubMed.

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  1. This paper provides insight into a potentially novel mechanism of Aβ toxicity. The authors start by looking for proteins in which phosphorylation is induced by toxic levels of Aβ in human cortical cultures. They identify the FISH (for Five SH3 domains) protein as being phosphorylated within one hour of Aβ treatment, indicating that this is an early event induced by Aβ. FISH can bind to the ADAM family of disintegrin metalloproteases via one of its SH3 domains, leading to activation of the ADAMs protease activity. Phosphorylation of FISH leads to a change in its distribution from the cytoplasmic to perinuclear region, allowing it to activate ADAM. Expression of a FISH construct without the ADAM binding SH3 domain protects against Aβ toxicity, suggesting FISH activation of ADAM is important in this process. The authors then focus on ADAM12, a known target of FISH, and show that ADAM12 may be activated by Aβ expression of an ADAM12 construct that lacks the protease domain protects against Aβ induced cell death, suggesting that ADAM12s protease activity has an important role.

    Two fundamental questions remain: How does Aβ lead to FISH phosphorylation and how does increased ADAM activity lead to cell death? The ADAM family is implicated in the processing of many transmembrane proteins including cytokines, growth factors, and of course APP. Does ADAM12 cleave a specific substrate that leads to cell death? It is not clear if ADAM12 can cleave APP at the α site (ADAMs 9, 10, and 17 are implicated so far). ADAM17 can release TNFα, which can lead to cell death via activation of the TNFα receptor signaling pathway. It would be interesting to determine if ADAM12 also has this activity, as TNFα is increased in Alzheimer disease brain and the signaling pathway has been implicated in Aβ toxicity (Li et al., 2004).

    Aβ toxicity can also be modulated by factors that protect against a range of cellular insults, for example, caspase inhibitors and antioxidants. It is not clear if the pathway described here is related to these global protective pathways or is selective for Aβ toxicity. It would thus be useful to know if ADAM12 modulates free radical toxicity, serum-deprivation-induced apoptosis, glutamate toxicity, etc.

    View all comments by Bruce Yankner
  2. I think we are getting off track abit. It has been established for some time that various phosphorylation processes occur in the presence of amyloid beta, including tau protein, tyrosine kinase receptors, involvement of g protins, etc... amongst others. These observations made here in this paper are interesting, but are not going to help in finding a cure for AD.

    References:
    Fundamentals of Biochemistry, Molecular Biology of the Cell, Genes7 and Alzforum.

    View all comments by Jacob Mack

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  1. There’s Something FISHy About Aβ Toxicity