. A peptide zipcode sufficient for anterograde transport within amyloid precursor protein. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16532-7. PubMed.

Recommends

Please login to recommend the paper.

Comments

Make a Comment

To make a comment you must login or register.

Comments on Primary Papers and News

  1. The study of the biology of APP and its proteolytic products, although pioneered in the early 1990s by Eddie Koo, Joseph Buxbaum, Sam Sisodia, and others, has nevertheless remained mostly out of the limelight until the last few years. The present study from Elaine Bearer’s laboratory now illuminates part of a picture that has been taking shape in the last few years suggesting that APP is likely involved in the modulation of synaptic activity in adults (Priller et al., 2006; Yang et al., 2005; Seabrook et al., 1999), in synapse formation and function (Wang et al., 2005), and in neuronal migration and adhesion during development (Herms et al., 2004).

    APP is a synaptic protein that is anterogradely transported to terminals. A few years ago Kamal et al. suggested that the C-terminus of APP could serve as a receptor for kinesin (Kamal et al., 2000), but this observation was subsequently questioned by Lazarov et al. (Lazarov et al., 2005). The present study by Satpute-Krishnan et al. provides strong evidence that the C-terminus of APP may indeed contain sequences sufficient for its association with axonal transport components. The careful experiments addressed this question using a fairly well-defined system, the squid giant axon, and the investigators’ observations indicate that the C-terminal domain of APP, either through a direct interaction with kinesin or indirectly via scaffolding proteins such as JIPs, participates in fast anterograde axonal transport. Quoting their discussion, “The robust motility of C99 beads in the intact axon argues for a physiological role of APP in recruitment of anterograde transport machinery inside cells.” It certainly does, and it comes as no surprise. Although the study by Satpute-Krishnan et al. does not answer the question of whether the interaction of APP with kinesin is or is not direct, it significantly adds to the rapidly growing evidence suggesting a crucial role of the C-terminus of APP (and possibly its family members APLP1 and 2) in neuronal biology, possibly at synaptic sites.

    The remarkable conservation of the C-terminal sequences of APP across phyla suggests conservation of function. Supporting this idea, the phenotypes of APP/APLP2 double and APP/APLP1/APLP2 triple knockouts and those of two prominent APP-interacting proteins (X11 and the Fe65 family) involve alterations in neuronal function, synaptic formation, function, and regulation (Wang et al., 2005; Ho et al., 2003; Yang et al., 2005; Priller et al., 2006), and in the case of the Fe65/FE65L double and APP/APLP1/APLP2 triple knockouts, result in cortical dysplasias and heterotopias (Herms et al., 2004, Guenette et al., 2006). Interestingly, it was recently shown that transgenic expression of AICD in combination with Fe65 causes alterations in signaling (Ryan and Pimplikar, 2005) and activation of proteins involved in growth cone collapse and axonal guidance.

    Why is this important? Most of all, because a significant component of amyloid-β toxicity requires multimerization of APP and cleavage of its C-terminus at Asp664 (Lu et al., 2003; Lu et al., 2003; Shaked et al., 2006). This cleavage not only releases a toxic peptide, but also removes the sequences required for the formation of a multiplicity of protein complexes at APP’s cytoplasmic domain, and as Satpute-Krishnan now suggest, for fast axonal transport. Consistent with what may be an important role of the extreme C-terminal sequences of APP in transducing amyloid-β toxicity, we recently showed that stabilization of APP’s cytoplasmic tail by mutation of the Asp664 cleavage site had a dramatic effect in the development of AD-like deficits in transgenic mice (Galvan et al., 2006)—even in the presence of abundant amyloid-β. With this in mind, the question arises as to whether cleavage at Asp664 while in transit towards synaptic sites would, as expected, prevent delivery of the molecule to its destination—and if the hypothesis of Kamal et al. is correct, whether it would affect the delivery of any subset of associated axonal transport vesicles. Thus, a population of Asp664-intact (transport-competent) and Asp664-cleaved (transport-incompetent) APP molecules may exist. Satpute-Krishnan et al. estimate that 3,000 copies of APP may be associated with each motile bead in their system; although in this study they don’t address the question of what is the minimal number of APP molecules required for transport, it is conceivable that transport-incompetent (Asp664-cleaved) APP molecules may be “carried along” in vesicles containing a sufficient number of transport-competent (Asp664-intact) APP. Cleavage of APP at Asp664 would thus affect not only the transport-competence (and thus the rate of delivery) of APP to neuronal terminals, but since the motifs required for the interaction of APP with a variety of cellular functions reside downstream of Asp664, it would also affect the overall signaling ability of populations of APP molecules at their destination at synaptic sites.

    References:

    . Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci. 2006 Jul 5;26(27):7212-21. PubMed.

    . Reduced synaptic vesicle density and active zone size in mice lacking amyloid precursor protein (APP) and APP-like protein 2. Neurosci Lett. 2005 Aug 12-19;384(1-2):66-71. PubMed.

    . Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology. 1999 Mar;38(3):349-59. PubMed.

    . Defective neuromuscular synapses in mice lacking amyloid precursor protein (APP) and APP-Like protein 2. J Neurosci. 2005 Feb 2;25(5):1219-25. PubMed.

    . Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members. EMBO J. 2004 Oct 13;23(20):4106-15. PubMed.

    . Axonal transport of amyloid precursor protein is mediated by direct binding to the kinesin light chain subunit of kinesin-I. Neuron. 2000 Nov;28(2):449-59. PubMed.

    . Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J Neurosci. 2005 Mar 2;25(9):2386-95. PubMed.

    . A role for Mints in transmitter release: Mint 1 knockout mice exhibit impaired GABAergic synaptic transmission. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1409-14. Epub 2003 Jan 23 PubMed.

    . Essential roles for the FE65 amyloid precursor protein-interacting proteins in brain development. EMBO J. 2006 Jan 25;25(2):420-31. PubMed.

    . Activation of GSK-3 and phosphorylation of CRMP2 in transgenic mice expressing APP intracellular domain. J Cell Biol. 2005 Oct 24;171(2):327-35. PubMed.

    . Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity. J Neurochem. 2003 Nov;87(3):733-41. PubMed.

    . Amyloid beta protein toxicity mediated by the formation of amyloid-beta protein precursor complexes. Ann Neurol. 2003 Dec;54(6):781-9. PubMed.

    . Abeta induces cell death by direct interaction with its cognate extracellular domain on APP (APP 597-624). FASEB J. 2006 Jun;20(8):1254-6. PubMed.

    . Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7130-5. PubMed.

    View all comments by Veronica Galvan
  2. This is an important study that may usher in a new perspective on the normal function of APP and clarify its role in AD pathogenesis.

This paper appears in the following:

News

  1. The Skinny on FAT: APP’s Role in Fast Axonal Transport