Amyloid precursor protein traffics from the Golgi directly to early endosomes in an Arl5b‐ and AP4‐dependent pathway
Open accessAbstract
The intracellular trafficking and proteolytic processing of the membrane‐bound amyloid precursor protein (APP) are coordinated events leading to the generation of pathogenic amyloid‐beta (Aβ) peptides. The membrane transport of newly synthesized APP from the Golgi to the endolysosomal system is not well defined, yet it is likely to be critical for regulating its processing by β‐secretase (BACE1) and γ‐secretase. Here, we show that the majority of newly synthesized APP is transported from the trans‐Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface. We show that Arl5b, a small G protein localized to the TGN, and AP4 are essential for the post‐Golgi transport of APP to early endosomes. Arl5b is physically associated with AP4 and is required for the recruitment of AP4, but not AP1, to the TGN. Depletion of either Arl5b or AP4 results in the accumulation of APP, but not BACE1, in the Golgi, and an increase in APP processing and Aβ secretion. These findings demonstrate that APP is diverted from BACE1 at the TGN for direct transport to early endosomes and that the TGN represents a site for APP processing with the subsequent secretion of Aβ.
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Highest BACE1 activity is detected in acidic compartments along the secretory and endocytic pathways including endosomes and trans-Golgi.
“which is consistent with highest BACE1 activity being detected in acidic compartments along the secretory and endocytic pathways including the endosomes and trans-Golgi (Bennett et al., 2000; Huse et al., 2000, 2002; Toh et al., 2017, 2018).”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
The Introduction identifies early endosomes as a major site of APP processing by BACE1, and the Discussion says the slightly acidic trans-Golgi network provides favourable conditions for BACE1 cleavage. The paper supports activity in those compartments, but does not establish that BACE1 activity is highest there. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe TGN is a major site for Aβ production along the secretory pathway.
“We and others have shown that the TGN is a major site for Aβ production along the secretory pathway (Burgos et al., 2010; Toh et al., 2017).”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
The Discussion reports that blocking APP export from the TGN increases Aβ production and suggests that Aβ can be generated there. It calls the TGN a potentially important site, but does not establish that it is a major site of Aβ production along the secretory pathway under normal conditions. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPP TGN-to-early endosome transport is regulated by AP-4 and Arl5b.
“a transport step regulated by the adaptor AP-4 and the small G protein Arl5b (Burgos et al., 2010; Toh et al., 2017).”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
Post-Golgi export of BACE1 is independent of the Arl5b/AP-4 sorting pathway.
“As the post-Golgi export of BACE1 is independent of the Arl5b/AP-4 sorting pathway”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
Newly synthesized APP traffics directly from the TGN to early endosomes.
“We have previously shown that newly synthesized APP traffics directly from the TGN to the early endosomes (Toh et al., 2017)”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
Depletion of Arl5b or AP-4 leads to accumulation of APP, but not BACE1, in the TGN.
“The depletion of either Arl5b or AP-4 leads to the accumulation of APP, but not BACE1, in the TGN.”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
Arl5b/AP-4 depletion increases APP processing by endogenous BACE1.
“Arl5b/AP-4 depletion also resulted in an increase in APP processing by endogenous BACE1”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
Depletion of Arf1 or Arf4 does not affect recruitment of AP-4 to the TGN.
“We have previously shown that depletion of Arf1 or Arf4 does not affect recruitment of AP-4 to the TGN (Toh et al., 2017).”
From Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production (2020) · cites this paper as Toh et al., 2017
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Cites
White, A. R., Du, T., Laughton, K. M., Volitakis, I., Sharples, R. A., Xilinas, M. E., Hoke, D. E., Holsinger, R. M. D., Evin, G., Cherny, R. A., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602487200 · Cited by 284 · see citing works
Muhammad, A., Flores, I., Zhang, H., Yu, R., Staniszewski, A., Planel, E., Herman, M., Ho, L., Kreber, R., Honig, L. S., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802545105 · Cited by 248 · see citing works
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Research works printed but not linked: 49
- Sisodia SS. Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci U S A. 1992;89(13):6075-6079.
- Skovronsky DM, Moore DB, Milla ME, Doms RW, Lee VMY. Protein kinase C-dependent alpha-secretase competes with beta-secretase for cleavage of amyloid- beta precursor protein in the trans-Golgi network. Journal of Biological Chemistry. 2000;275(4):2568- 2575.
- Thinakaran G, Koo EH. Amyloid precursor protein trafficking, processing, and function. J Biol Chem. 2008;283(44):29615-29619.
- Rajendran L, Honsho M, Zahn TR, et al. Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006;103(30):11172-11177.
- Small SA, Gandy S. Sorting through the cell biology of Alzheimer's disease: intracellular pathways to pathogenesis. Neuron. 2006;52(1):15-31.
- Xu H, Sweeney D, Wang R, et al. 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;94(8):3748-3752.
- Siman R, Velji J. Localization of presenilin-nicastrin complexes and gamma-secretase activity to the trans- Golgi network. J Neurochem. 2003;84(5):1143-1153.
- Burgos PV, Mardones GA, Rojas AL, et al. Sorting of the Alzheimer's disease amyloid precursor protein mediated by the AP-4 complex. Dev Cell. 2010;18(3):425-436.
- Choy RW, Cheng Z, Schekman R. Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid beta (Abeta) production in the trans-Golgi network. Proc Natl Acad Sci U S A. 2012;109(30):E2077-E2082.
- Huse JT, Doms RW. Neurotoxic traffic: uncovering the mechanics of amyloid production in Alzheimer's disease. Traffic. 2001;2(2):75-81.
- Toh WH, Gleeson PA. Dysregulation of intracellular trafficking and endosomal sorting in Alzheimer's disease: controversies and unanswered questions. Biochem J. 2016;473(14):1977-1993.
- Walter J, Haass C. Posttranslational modifications of amyloid precursor protein : ectodomain phosphorylation and sulfation. Methods Mol Med. 2000;32:149-168.
- De Matteis MA, Luini A. Exiting the Golgi complex. Nat Rev Mol Cell Biol. 2008;9(4):273-284.
- Goud B, Gleeson PA. TGN golgins, Rabs and cytoskeleton: regulating the Golgi trafficking highways. Trends Cell Biol. 2010;20(6):329-336.
- Robinson MS. Adaptable adaptors for coated vesicles. Trends in Cell Biology. 2004;14(4):167-174.
- Lock JG, Hammond LA, Houghton F, Gleeson PA, Stow JL. E-cadherin transport from the trans-Golgi network in tubulovesicular carriers is selectively regulated by golgin-97. Traffic. 2005;6(12):1142-1156.
- Lieu ZZ, Lock JG, Hammond LA, La Gruta NL, Stow JL, Gleeson PA. A trans-Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo. Proc Natl Acad Sci U S A. 2008;105(9):3351-3356.
- Kametaka S, Waguri S. Visualization of TGN-endosome trafficking in mammalian and Drosophila cells. Methods Enzymol. 2012;504:255-271.
- Schmid SL. Clathrin-coated vesicle formation and protein sorting: an integrated process. Annu Rev Biochem. 1997;66:511-548.
- Marks MS, Woodruff L, Ohno H, Bonifacino JS. Protein targeting by tyrosine-and di-leucine-based signals: evidence for distinct saturable components. J Cell Biol. 1996;135(2):341-354.
- Borg JP, Ooi J, Levy E, Margolis B. The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein. Mol Cell Biol. 1996;16(11):6229- 6241.
- Nordeng TW, Bakke O. Overexpression of proteins containing tyrosine-or leucine-based sorting signals affects transferrin receptor trafficking. J Biol Chem. 1999;274(30):21139-21148.
- Lee MS, Kao SC, Lemere CA, et al. APP processing is regulated by cytoplasmic phosphorylation. J Cell Biol. 2003;163(1):83-95.
- Boehm M, Aguilar RC, Bonifacino JS. Functional and physical interactions of the adaptor protein complex AP- 4 with ADP-ribosylation factors (ARFs). EMBO J. 2001;20(22):6265-6276.
- Rogelj B, Mitchell JC, Miller CC, McLoughlin DM. The X11/Mint family of adaptor proteins. Brain research reviews. 2006;52(2):305-315.
- Miller CC, McLoughlin DM, Lau KF, Tennant ME, Rogelj B. The X11 proteins, Abeta production and Alzheimer's disease. Trends Neurosci. 2006;29(5):280- 285.
- Chia PZ, Toh WH, Sharples R, Gasnereau I, Hill AF, Gleeson PA. Intracellular Itinerary of Internalised beta- Secretase, BACE1, and Its Potential Impact on beta- Amyloid Peptide Biogenesis. Traffic. 2013;14(9):997- 1013.
- von Kleist L, Stahlschmidt W, Bulut H, et al. Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. Cell. 2011;146(3):471-484.
- Nakai W, Kondo Y, Saitoh A, Naito T, Nakayama K, Shin HW. ARF1 and ARF4 regulate recycling endosomal morphology and retrograde transport from endosomes to the Golgi apparatus. Molecular Biology of the Cell. 2013;24(16):2570-2581.
- Houghton FJ, Bellingham SA, Hill AF, et al. Arl5b is a Golgi-localised small G protein involved in the regulation of retrograde transport. Exp Cell Res. 2012;318(5):464-477.
- Chia PZ, Ramdzan YM, Houghton FJ, Hatters DM, Gleeson PA. High-throughput quantitation of intracellular trafficking and organelle disruption by flow cytometry. Traffic. 2014;15(5):572-582.
- Toh WH, Houghton FJ, Chia PZ, Ramdzan YM, Hatters DM, Gleeson PA. Application of flow cytometry to analyze intracellular location and trafficking of cargo in cell populations. Methods in molecular biology. 2015;1270:227-238.
- Vardarajan BN, Bruesegem SY, Harbour ME, et al. Identification of Alzheimer disease-associated variants in genes that regulate retromer function. Neurobiol Aging. 2012;33(9):2231 e2215-2231 e2230.
- Ginsberg SD, Mufson EJ, Alldred MJ, et al. Upregulation of select rab GTPases in cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease. Journal of chemical neuroanatomy. 2011;42(2):102-110.
- Small SA, Kent K, Pierce A, et al. Model-guided microarray implicates the retromer complex in Alzheimer's disease. Ann Neurol. 2005;58(6):909-919.
- Rogaeva E, Meng Y, Lee JH, et al. The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet. 2007;39(2):168-177.
- Scherzer CR, Offe K, Gearing M, et al. Loss of apolipoprotein E receptor LR11 in Alzheimer disease. Arch Neurol. 2004;61(8):1200-1205.
- Andersen OM, Reiche J, Schmidt V, et al. Neuronal sorting protein-related receptor sorLA/LR11 regulates processing of the amyloid precursor protein. Proc Natl Acad Sci U S A. 2005;102(38):13461-13466.
- Small SA, Petsko GA. Retromer in Alzheimer disease, Parkinson disease and other neurological disorders. Nat Rev Neurosci. 2015;16(3):126-132.
- Siegenthaler BM, Rajendran L. Retromers in Alzheimer's disease. Neuro-degenerative diseases. 2012;10(1-4):116-121.
- Berman DE, Ringe D, Petsko GA, Small SA. The use of pharmacological retromer chaperones in Alzheimer's disease and other endosomal-related disorders. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2015;12(1):12-18.
- Dell'Angelica EC, Mullins C, Bonifacino JS. AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem. 1999;274(11):7278-7285.
- Hirst J, Bright NA, Rous B, Robinson MS. Characterization of a fourth adaptor-related protein complex. Mol Biol Cell. 1999;10(8):2787-2802.
- Haass C, Kaether C, Thinakaran G, Sisodia S. Trafficking and proteolytic processing of APP. Cold Spring Harbor perspectives in medicine. 2012;2(5):a006270.
- Caster AH, Kahn RA. Recruitment of the Mint3 adaptor is necessary for export of the amyloid precursor protein (APP) from the Golgi complex. J Biol Chem. 2013;288(40):28567-28580.
- Luke MR, Kjer-Nielsen L, Brown DL, Stow JL, Gleeson PA. GRIP domain-mediated targeting of two new coiled-coil proteins, GCC88 and GCC185, to subcompartments of the trans-Golgi network. J Biol Chem. 2003;278(6):4216-4226.
- Janvier K, Bonifacino JS. Role of the endocytic machinery in the sorting of lysosome-associated membrane proteins. Mol Biol Cell. 2005;16(9):4231- 4242.
- Southon A, Greenough M, Hung YH, Norgate M, Burke R, Camakaris J. The ADP-ribosylation factor 1 (Arf1) is involved in regulating copper uptake. Int J Biochem Cell Biol. 2011;43(1):146-153.
- Woodcroft BJ, Hammond L, Stow JL, Hamilton NA. Automated organelle-based colocalization in whole-cell imaging. Cytometry A. 2009;75(11):941-950.
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Bis, J. C., Jian, X., Kunkle, B. W., Chen, Y., Hamilton-Nelson, K. L., Bush, W. S., Salerno, W. J., Lancour, D., Ma, Y., Renton, A. E., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-018-0112-7 · Cited by 248 · see citing works
Tan, J. Z. A., Fourriere, L., Wang, J., Perez, F., Boncompain, G., & Gleeson, P. A. (2020) · Molecular Biology of the Cell · doi:10.1091/mbc.e19-09-0487 · Cited by 37 · see citing works
Self-citationAging impact on amyloid precursor protein neuronal trafficking
Burrinha, T., & Guimas Almeida, C. (2022) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2022.102524 · Cited by 26 · see citing works
- Authors
- Toh, W. H., Tan, J. Z. A., Zulkefli, K. L., Houghton, F. J., & Gleeson, P. A.
- Affiliations
- The University of Melbourne (AU)
- Corresponding author
- Gleeson, Paul A.
- Venue
- Traffic
- Publisher
- Wiley
- Published
- 2017-01-30
- Volume
- 18
- Issue
- 3
- Pages
- 159-175
- ISSN
- 1398-9219 (ISSN-L)
- 1600-0854
- OpenAlex
- W2562852452
- Cited by
- 75
- References
- 2
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 9 · 2019: 11 · 2018: 6 · 2017: 4
- FWCI
- 4.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- public-domain
- onlinelibrary.wiley.com/termsAndConditions#vor (vor)
- Locations
- Traffic (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- University of Melbourne
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- amyloid precursor protein, Golgi apparatus, early endosomes, trans-Golgi network, post-Golgi trafficking, amyloid-beta secretion, beta-secretase, gamma-secretase, APP processing, small GTPases, endolysosomal trafficking
- MeSH terms
- Cell Membrane, DNA-Binding Proteins, Golgi Apparatus, HeLa Cells, Humans, Lysosomes, Protein Processing, Post-Translational, Endosomes, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, RNA-Binding Proteins, ADP-Ribosylation Factors, Protein Transport, trans-Golgi Network, Transport Vesicles, Cell Line, Tumor, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Amyloid Precursor Protein Secretases
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