Matrone C, Marolda R, Ciafrè S, Ciotti MT, Mercanti D, Calissano P. Tyrosine kinase nerve growth factor receptor switches from prosurvival to proapoptotic activity via Abeta-mediated phosphorylation. Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11358-63. PubMed.

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  1. I'm not sure the impact of β- and γ-secretase inhibitors in this system confirms a role for Aβ. The authors themselves are careful to refrain from that conclusion. Indeed, some of their data "points to the possibility that Aβ, when externally added, may activate different unknown mechanism(s) of death." It is quite likely that the relevant γ-secretase substrate here is p75 rather than APP. And though it is not clear precisely which β-secretase inhibitors were used, they all have questionable specificity; even if specific for BACE1, this enzyme has predictable activity against substrates other than APP. According to sequence requirements determined by Grüninger-Leitch et al. (2002), an intriguing candidate is transmembrane protein 132A (aka, GRP78-binding protein), a brain protein shown to protect neuro2A cells against trophic-factor withdrawal (Oh-hashi et al., 2003). Among others is FOXO3a, recently found to be broadly neuroprotective (Mojsilovic-Petrovic et al., 2009).

    References:

    Grüninger-Leitch F, Schlatter D, Küng E, Nelböck P, Döbeli H. Substrate and inhibitor profile of BACE (beta-secretase) and comparison with other mammalian aspartic proteases. J Biol Chem. 2002 Feb 15;277(7):4687-93. PubMed.

    Mojsilovic-Petrovic J, Nedelsky N, Boccitto M, Mano I, Georgiades SN, Zhou W, Liu Y, Neve RL, Taylor JP, Driscoll M, Clardy J, Merry D, Kalb RG. FOXO3a is broadly neuroprotective in vitro and in vivo against insults implicated in motor neuron diseases. J Neurosci. 2009 Jun 24;29(25):8236-47. PubMed.

    Oh-hashi K, Naruse Y, Amaya F, Shimosato G, Tanaka M. Cloning and characterization of a novel GRP78-binding protein in the rat brain. J Biol Chem. 2003 Mar 21;278(12):10531-7. PubMed.

    View all comments by Steve Barger

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