. Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1. J Biol Chem. 2009 May 1;284(18):12145-52. PubMed.


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  1. It has been well suggested that APP is processed during its intracellular trafficking to generate APP CTFs, Aβ, and the APP intracellular domain (AICD). However, how these APP derivatives are transported intracellularly is much less known. In this paper by Zoia Muresan and colleagues, the authors utilized various antibodies against different APP domains for immunocytochemistry and found that full-length APP and APP derivatives are sorted into distinct vesicles and transported independently, with APP CTFs preferentially entering the lamellipodium and filopodia of growth cones and becoming concentrated in regions of growth cone turning and advancement.

    In some experiments, the authors used antibody 22C11 for detecting the extracellular fragment of APP and antibody 4G8 for Aβ. Since 22C11 cross-reacts with other APP family proteins (APLP1 and APLP2) while 4G8 only sees APP (and Aβ), the comparisons for the localizations of full-length APP and its derivatives (especially Aβ) may not be appropriate. Nevertheless, these results are very interesting and suggest that a large amount of APP can be cleaved before it is sorted into axonal transport vesicles, probably at the ER and the Golgi/TGN, as we have reported before (Xu et al., 1997 and Greenfield et al., 1999). Moreover, the results indicate that full-length APP and its derivatives may be transported to different locations and exert distinct functions. Several studies from Larry Goldstein and William Mobley’s labs have already suggested that APP plays an active role in axonal transport. Our very recent study also found that both full-length APP and APP bCTF (C99) can regulate intracellular trafficking of PS1/β-secretase components for their cell surface delivery (the results, Liu et al., 2009, are also commented on in this Research News). However, whether or not the intracellular trafficking of proteins other than PS1/γ-secretase components may be regulated by APP awaits further examination. Further, whether the distinct sorting paths or localizations of APP and its derivatives may differentially direct the transport of their respective “cargos,” especially at growth cones also deserves careful scrutiny.


    . Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3748-52. PubMed.

    . Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):742-7. PubMed.

    . Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1. J Biol Chem. 2009 May 1;284(18):12145-52. PubMed.

    View all comments by Yunwu Zhang
  2. We read with great interest the paper by Liu et al. (1), and would like to comment on their exciting findings. The paper proposes a novel mechanism by which the amyloid-β precursor protein (APP) could regulate the intracellular transport of a select group of proteins with emphasis on those that form the γ-secretase complex.

    APP was previously proposed to regulate the intraneuronal transport by functioning as a receptor for the microtubule motor kinesin-1. However, it is still largely debated to what extent this model is relevant in vivo, and whether the interaction between APP and kinesin-1 is direct or mediated by bridging protein(s), such as JIP-1 (cJun NH2-terminal kinase-interacting protein-1). Related questions are now addressed by two papers: Liu et al. (1), and our paper, Muresan et al. (2), which are the subject of this Research News. Both articles show that the transport of APP, and the role of APP in regulating transport of other cargo proteins, are far more complex than previously anticipated.

    Liu et al. (1) propose that APP could modulate the delivery of the γ-secretase complex to the cell surface by regulating its exit from the trans-Golgi network (TGN). A possible mechanism is that APP interacts with the γ-secretase complex and prevents it from being recruited into cargo vesicles, at the TGN. A direct consequence of this mechanism is that APP regulates in this way the cleavage by γ-secretase of substrates localized to the cell surface, such as Notch. Implicitly, Notch signaling is regulated by APP in this way. Liu et al. (1) also show that the trafficking of γ-secretase to the cell surface is regulated not only by APP, but also by the activity of phospholipase D1 (PLD1), a lipid-modifying enzyme that converts phosphatidylcholine to phosphatidic acid. Intriguingly, PLD1 also regulates the transport of APP in a presenilin-1 (PS1, a component of the γ-secretase complex) independent manner. This is important, because several groups reported that PS1 regulates the axonal transport by mechanisms that are not fully understood. Although more work needs to be done to elucidate the complex regulation of the transport of APP and its processing machinery, Liu et al. (1) bring an exciting contribution into this picture.

    As perceived from the articles of Liu et al. (1) and of Muresan et al. (2), full-length APP is largely restricted to the intracellular compartments of the early secretory pathway. Biochemical data recently obtained with mouse brain (3) certainly support this scenario. In spite of this, a fraction of full-length APP does reach the plasma membrane, and full-length APP may also have functions at the plasma membrane. However, a significant fraction of it is cleaved prior to entering the cargo vesicles that transport APP (or, rather, its fragments) to various intracellular destinations, as shown by us (2).

    We would like to comment on the specificity of the antibody 22C11 (4), an issue raised by Drs. Xu and Zhang in their comment to our paper. This antibody, largely used to detect full-length APP and the soluble N-terminal fragments (sAPPs), was used in some of our immunolabeling experiments due to its high sensitivity. We are aware that this antibody may cross-react with the amyloid precursor-like proteins (APLP1 and APLP2), although with lower affinity. To circumvent this problem, along with 22C11, we employed a plethora of antibodies recognizing epitopes from various regions of APP polypeptide, including antibodies that do not cross-react with APLP1 or APLP2, such as Alz90 (Roche; recognizing residues 511-608 of APP, poorly conserved in APLPs).

    With regard to antibody 4G8, which also recognizes the full-length APP, in addition to cleaved fragments, in our study we included antibodies against the cleaved C-terminal ends of Aβ40 and Aβ42, which selectively detect the Aβ fragments. Although our study was not aimed at the precise identification of the APP-derived polypeptides that are transported within neuritis, our results indicate that the transport of APP within neurites occurs to a large extent as cleaved fragments generated by proteolytic processing of APP in the cell body. Thus, the most important idea that derives from our study is that each APP fragment has a life of its own that begins early in the secretory pathway, and may thus have functions that are largely independent from that of full-length APP. Thus, we think that APP is indeed an “All Purpose Protein” (a term that we first heard from Dr. Sangram Sisodia, during a seminar talk) which functions as full-length protein and also as cleaved fragments.


    . Intracellular trafficking of presenilin 1 is regulated by beta-amyloid precursor protein and phospholipase D1. J Biol Chem. 2009 May 1;284(18):12145-52. PubMed.

    . The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. J Neurosci. 2009 Mar 18;29(11):3565-78. PubMed.

    . The in vivo brain interactome of the amyloid precursor protein. Mol Cell Proteomics. 2008 Jan;7(1):15-34. PubMed.

    . Amyloid-like properties of peptides flanking the epitope of amyloid precursor protein-specific monoclonal antibody 22C11. J Biol Chem. 1993 Dec 15;268(35):26571-7. PubMed.

    View all comments by Virgil Muresan

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