. Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci. 2009 Jun 10;29(23):7459-73. PubMed.


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  1. This very interesting paper provides another link in our understanding of the role of APP in synaptogenesis and Alzheimer's disease. Understanding the function of APP and its molecular partners (e.g., reelin) will undoubtedly provide key insights into the mechanisms of synaptic loss and disease progression, the role of ApoE, and the potential roles of reelin and the LDL receptor family in pathogenesis.

    Just to set the record straight, while the paper by Qiu et al. in J Neuroscience is undoubtedly important, there were several seminal papers from our group prior to the Qiu paper, which provided both in vitro and in vivo evidence that APP was involved in neurite outgrowth (Milward et al., 1992; Small et al., 1994; Williamson et al., 1995; Clarris et al., 1995).


    . The amyloid protein precursor of Alzheimer's disease is a mediator of the effects of nerve growth factor on neurite outgrowth. Neuron. 1992 Jul;9(1):129-37. PubMed.

    . A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth. J Neurosci. 1994 Apr;14(4):2117-27. PubMed.

    . Affinity purification of proteoglycans that bind to the amyloid protein precursor of Alzheimer's disease. J Neurochem. 1995 Nov;65(5):2201-8. PubMed.

    . Expression of the amyloid protein precursor of Alzheimer's disease in the developing rat olfactory system. Brain Res Dev Brain Res. 1995 Aug 28;88(1):87-95. PubMed.

  2. Work from several labs, including our own, has shown functions for APP in the developing nervous system, including roles in migration, neurite outgrowth, and synaptogenesis. Each of these functions implicates APP in mediating differential adhesion to extracellular factors. Our lab has shown that full-length APP acts through DAB1 to affect neuronal precursor cell migration into the cortical plate (Young-Pearse et al., 2007). In addition, we have addressed the mechanism by which APP affects neurite outgrowth by showing that APP and integrin β1 biochemically and functionally interact in embryonic rodent neurons (Young-Pearse et al., 2008). However, the extracellular factor(s) that APP is acting with to execute these functions previously had not been elucidated. This recent work by Hoe et al. begins to answer this key question by showing that Reelin interacts with APP to regulate neurite outgrowth. These data nicely complement the authors' previous studies showing an interaction between APP/ApoER2 and F-spondin (Hoe et al., 2005), another secreted factor expressed in the developing brain initially identified by the Südhof lab to biochemically interact with APP (Ho and Südhof, 2004). Together, these studies support a (speculative) model whereby the function of APP is determined by both its extracellular binding partner as well as by its dimerization state with itself or other type-I transmembrane domain proteins (ApoER2, ITGβ1, etc.).

    In addition to aiding in elucidating the mechanism by which APP functions during development, the authors also provide data that could suggest that the APP-Reelin interaction has some role in AD pathogenesis. The authors show that exogenously applied Reelin increases α-secretase cleavage while decreasing β-secretase cleavage and Aβ generation. In addition, the authors point out that Reelin protein and mRNA levels are decreased in AD brains. Based upon these data, the speculation would be that a loss of Reelin in aged brains would lead to an increase in Aβ production, and that this would lead to pathology. To address this possibility, it would be critical to examine whether a loss of endogenous Reelin (in knockout animals) significantly increases Aβ generation and plaque formation, and/or enhances the behavioral defects observed in APP transgenic animals.


    . Binding of F-spondin to amyloid-beta precursor protein: a candidate amyloid-beta precursor protein ligand that modulates amyloid-beta precursor protein cleavage. Proc Natl Acad Sci U S A. 2004 Feb 24;101(8):2548-53. PubMed.

    . F-spondin interaction with the apolipoprotein E receptor ApoEr2 affects processing of amyloid precursor protein. Mol Cell Biol. 2005 Nov;25(21):9259-68. PubMed.

    . Secreted APP regulates the function of full-length APP in neurite outgrowth through interaction with integrin beta1. Neural Dev. 2008;3:15. PubMed.

    . A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci. 2007 Dec 26;27(52):14459-69. PubMed.

    View all comments by Tracy Young-Pearse

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