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Cited by 69Alzheimer's disease research and treatmentsAutophagy in Disease and TherapyCellular transport and secretion

Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation

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Feng, Tuancheng, Tammineni, Prasad, Agrawal, Chanchal, Jeong, Yu Young, Cai, Qian·2017·Journal of Biological Chemistry
DOI 10.1074/jbc.m116.766584PMC PMC5290944
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Abstract

β-Site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is the major neuronal β-secretase for amyloid-β generation and is degraded in lysosomes. The autophagy-lysosomal system plays a key role in the maintenance of cellular homeostasis in neurons. Recent studies established that nascent autophagosomes in distal axons move predominantly in the retrograde direction toward the soma, where mature lysosomes are mainly located. However, it remains unknown whether autophagy plays a critical role in regulation of BACE1 trafficking and degradation. Here, we report that induction of neuronal autophagy enhances BACE1 turnover, which is suppressed by lysosomal inhibition. A significant portion of BACE1 is recruited to the autophagy pathway and co-migrates robustly with autophagic vacuoles along axons. Moreover, we reveal that autophagic vacuole-associated BACE1 is accumulated in the distal axon of Alzheimer's disease-related mutant human APP transgenic neurons and mouse brains. Inducing autophagy in mutant human APP neurons augments autophagic retention of BACE1 in distal axons, leading to enhanced β-cleavage of APP. This phenotype can be reversed by Snapin-enhanced retrograde transport, which facilitates BACE1 trafficking to lysosomes for degradation. Therefore, our study provides new insights into autophagy-mediated regulation of BACE1 turnover and APP processing, thus building a foundation for future development of potential Alzheimer's disease therapeutic strategies.

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  1. [1]1. Cai, H. ∙ Wang, Y. ∙ McCarthy, D. ... BACE1 is the major β-secretase for generation of Aβ peptides by neurons Nat. Neurosci. 2001; 4:233-234 Crossref Scopus (990) PubMed Google Scholar
  2. [2]2. Sinha, S. ∙ Anderson, J.P. ∙ Barbour, R. ... Purification and cloning of amyloid precursor protein β-secretase from human brain Nature. 1999; 402:537-540 Crossref Scopus (1514) PubMed Google Scholar
  3. [3]3. Vassar, R. ∙ Bennett, B.D. ∙ Babu-Khan, S. ... β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE Science. 1999; 286:735-741 Crossref Scopus (3455) PubMed Google Scholar
  4. [4]4. Yan, R. ∙ Bienkowski, M.J. ∙ Shuck, M.E. ... Membrane-anchored aspartyl protease with Alzheimer’s disease β-secretase activity Nature. 1999; 402:533-537 Crossref Scopus (1363) PubMed Google Scholar
  5. [6]6. Yang, L.B. ∙ Lindholm, K. ∙ Yan, R. ... Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease Nat. Med. 2003; 9:3-4 Crossref Scopus (627) PubMed Google Scholar
  6. [7]7. Vassar, R. ∙ Kovacs, D.M. ∙ Yan, R. ... The β-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential J. Neurosci. 2009; 29:12787-12794 Crossref Scopus (474) PubMed Google Scholar
  7. [8]8. Willem, M. ∙ Lammich, S. ∙ Haass, C. Function, regulation and therapeutic properties of β-secretase (BACE1) Semin. Cell Dev. Biol. 2009; 20:175-182 Crossref Scopus (77) PubMed Google Scholar
  8. [9]9. Evin, G. ∙ Barakat, A. ∙ Masters, C.L. BACE: therapeutic target and potential biomarker for Alzheimer’s disease Int. J. Biochem. Cell Biol. 2010; 42:1923-1926 Crossref Scopus (62) PubMed Google Scholar
  9. [10]10. Huse, J.T. ∙ Pijak, D.S. ∙ Leslie, G.J. ... Maturation and endosomal targeting of β-site amyloid precursor protein-cleaving enzyme. The Alzheimer’s disease β-secretase J. Biol. Chem. 2000; 275:33729-33737 Full Text Full Text (PDF) Scopus (386) PubMed Google Scholar
  10. [11]11. He, X. ∙ Li, F. ∙ Chang, W.P. ... GGA proteins mediate the recycling pathway of memapsin 2 (BACE) J. Biol. Chem. 2005; 280:11696-11703 Full Text Full Text (PDF) Scopus (202) PubMed Google Scholar
  11. [13]13. Walter, J. ∙ Fluhrer, R. ∙ Hartung, B. ... Phosphorylation regulates intracellular trafficking of β-secretase J. Biol. Chem. 2001; 276:14634-14641 Full Text Full Text (PDF) Scopus (253) PubMed Google Scholar
  12. [14]14. Fukumoto, H. ∙ Cheung, B.S. ∙ Hyman, B.T. ... β-Secretase protein and activity are increased in the neocortex in Alzheimer disease Arch. Neurol. 2002; 59:1381-1389 Crossref Scopus (627) PubMed Google Scholar
  13. [15]15. Tesco, G. ∙ Koh, Y.H. ∙ Kang, E.L. ... Depletion of GGA3 stabilizes BACE and enhances β-secretase activity Neuron. 2007; 54:721-737 Full Text Full Text (PDF) Scopus (308) PubMed Google Scholar
  14. [16]16. Sannerud, R. ∙ Declerck, I. ∙ Peric, A. ... ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1 Proc. Natl. Acad. Sci. U.S.A. 2011; 108:E559-E568 Crossref Scopus (194) PubMed Google Scholar
  15. [17]17. Wu, J. ∙ Petralia, R.S. ∙ Kurushima, H. ... Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation Cell. 2011; 147:615-628 Full Text Full Text (PDF) Scopus (162) PubMed Google Scholar
  16. [18]18. Koh, Y.H. ∙ von Arnim, C.A. ∙ Hyman, B.T. ... BACE is degraded via the lysosomal pathway J. Biol. Chem. 2005; 280:32499-32504 Full Text Full Text (PDF) Scopus (147) PubMed Google Scholar
  17. [19]19. Lefort, R. ∙ Pozueta, J. ∙ Shelanski, M. Cross-linking of cell surface amyloid precursor protein leads to increased β-amyloid peptide production in hippocampal neurons: implications for Alzheimer’s disease J. Neurosci. 2012; 32:10674-10685 Crossref Scopus (32) PubMed Google Scholar
  18. [20]20. Ye, X. ∙ Cai, Q. Snapin-mediated BACE1 retrograde transport is essential for its degradation in lysosomes and regulation of APP processing in neurons Cell Rep. 2014; 6:24-31 Full Text Full Text (PDF) Scopus (47) PubMed Google Scholar
  19. [21]21. Overly, C.C. ∙ Hollenbeck, P.J. Dynamic organization of endocytic pathways in axons of cultured sympathetic neurons J. Neurosci. 1996; 16:6056-6064 Crossref PubMed Google Scholar
  20. [22]22. Cai, Q. ∙ Lu, L. ∙ Tian, J.H. ... Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons Neuron. 2010; 68:73-86 Full Text Full Text (PDF) Scopus (181) PubMed Google Scholar
  21. [23]23. Lee, S. ∙ Sato, Y. ∙ Nixon, R.A. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy J. Neurosci. 2011; 31:7817-7830 Crossref Scopus (371) PubMed Google Scholar
  22. [24]24. Xie, Y. ∙ Zhou, B. ∙ Lin, M.Y. ... Endolysosomal deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS mice Neuron. 2015; 87:355-370 Full Text Full Text (PDF) Scopus (128) PubMed Google Scholar
  23. [25]25. Yue, Z. ∙ Friedman, L. ∙ Komatsu, M. ... The cellular pathways of neuronal autophagy and their implication in neurodegenerative diseases Biochim. Biophys. Acta. 2009; 1793:1496-1507 Crossref Scopus (144) PubMed Google Scholar
  24. [26]26. Rubinsztein, D.C. ∙ Mariño, G. ∙ Kroemer, G. Autophagy and aging Cell. 2011; 146:682-695 Full Text Full Text (PDF) Scopus (1780) PubMed Google Scholar
  25. [27]27. Nixon, R.A. The role of autophagy in neurodegenerative disease Nat. Med. 2013; 19:983-997 Crossref Scopus (1535) PubMed Google Scholar
  26. [28]28. Schneider, J.L. ∙ Cuervo, A.M. Autophagy and human disease: emerging themes Curr. Opin. Genet. Dev. 2014; 26:16-23 Crossref Scopus (265) PubMed Google Scholar
  27. [30]30. Maday, S. ∙ Holzbaur, E.L. Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway Dev. Cell. 2014; 30:71-85 Full Text Full Text (PDF) Scopus (270) PubMed Google Scholar
  28. [31]31. Cheng, X.T. ∙ Zhou, B. ∙ Lin, M.Y. ... Axonal autophagosomes use the ride-on service for retrograde transport toward the soma Autophagy. 2015; 11:1434-1436 Crossref Scopus (25) PubMed Google Scholar
  29. [32]32. Cheng, X.T. ∙ Zhou, B. ∙ Lin, M.Y. ... Axonal autophagosomes recruit dynein for retrograde transport through fusion with late endosomes J. Cell Biol. 2015; 209:377-386 Crossref Scopus (163) PubMed Google Scholar
  30. [33]33. Maday, S. ∙ Holzbaur, E.L. Compartment-specific regulation of autophagy in primary neurons J. Neurosci. 2016; 36:5933-5945 Crossref Scopus (217) PubMed Google Scholar
  31. [34]34. Krüger, U. ∙ Wang, Y. ∙ Kumar, S. ... Autophagic degradation of τ in primary neurons and its enhancement by trehalose Neurobiol. Aging. 2012; 33:2291-2305 Crossref Scopus (226) PubMed Google Scholar
  32. [35]35. Su, Q. ∙ Cai, Q. ∙ Gerwin, C. ... Syntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons Nat. Cell Biol. 2004; 6:941-953 Crossref Scopus (128) PubMed Google Scholar
  33. [36]36. Tsvetkov, A.S. ∙ Miller, J. ∙ Arrasate, M. ... A small-molecule scaffold induces autophagy in primary neurons and protects against toxicity in a Huntington disease model Proc. Natl. Acad. Sci. U.S.A. 2010; 107:16982-16987 Crossref Scopus (226) PubMed Google Scholar
  34. [37]37. Wong, Y.C. ∙ Holzbaur, E.L. Autophagosome dynamics in neurodegeneration at a glance J. Cell Sci. 2015; 128:1259-1267 Crossref Scopus (97) PubMed Google Scholar
  35. [38]38. Nixon, R.A. ∙ Wegiel, J. ∙ Kumar, A. ... Extensive involvement of autophagy in Alzheimer disease: an immuno-electron microscopy study J. Neuropathol. Exp. Neurol. 2005; 64:113-122 Crossref Scopus (1258) PubMed Google Scholar
  36. [39]39. Mizushima, N. ∙ Noda, T. ∙ Yoshimori, T. ... A protein conjugation system essential for autophagy Nature. 1998; 395:395-398 Crossref Scopus (1366) PubMed Google Scholar
  37. [41]41. Suzuki, K. ∙ Kirisako, T. ∙ Kamada, Y. ... The pre-autophagosomal structure organized by concerted functions of APG genes is essential for autophagosome formation EMBO J. 2001; 20:5971-5981 Crossref Scopus (845) PubMed Google Scholar
  38. [42]42. Funderburk, S.F. ∙ Marcellino, B.K. ∙ Yue, Z. Cell “self-eating” (autophagy) mechanism in Alzheimer’s disease Mt. Sinai J. Med. 2010; 77:59-68 Crossref Scopus (103) PubMed Google Scholar
  39. [43]43. Nixon, R.A. ∙ Yang, D.S. Autophagy failure in Alzheimer’s disease–locating the primary defect Neurobiol. Dis. 2011; 43:38-45 Crossref Scopus (517) PubMed Google Scholar
  40. [45]45. Qing, H. ∙ Zhou, W. ∙ Christensen, M.A. ... Degradation of BACE by the ubiquitin-proteasome pathway FASEB J. 2004; 18:1571-1573 Crossref Scopus (142) PubMed Google Scholar
  41. [46]46. Prabhu, Y. ∙ Burgos, P.V. ∙ Schindler, C. ... Adaptor protein 2-mediated endocytosis of the β-secretase BACE1 is dispensable for amyloid precursor protein processing Mol. Biol. Cell. 2012; 23:2339-2351 Crossref Scopus (61) PubMed Google Scholar
  42. [47]47. Kang, E.L. ∙ Cameron, A.N. ∙ Piazza, F. ... Ubiquitin regulates GGA3-mediated degradation of BACE1 J. Biol. Chem. 2010; 285:24108-24119 Full Text Full Text (PDF) Scopus (92) PubMed Google Scholar
  43. [48]48. Yeates, E.F. ∙ Tesco, G. The endosome-associated deubiquitinating enzyme USP8 regulates BACE1 enzyme ubiquitination and degradation J. Biol. Chem. 2016; 291:15753-15766 Full Text Full Text (PDF) Scopus (56) PubMed Google Scholar
  44. [49]49. Yu, W.H. ∙ Cuervo, A.M. ∙ Kumar, A. ... Macroautophagy–a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease J. Cell Biol. 2005; 171:87-98 Crossref Scopus (875) PubMed Google Scholar
  45. [53]53. Sarkar, S. ∙ Perlstein, E.O. ∙ Imarisio, S. ... Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models Nat. Chem. Biol. 2007; 3:331-338 Crossref Scopus (526) PubMed Google Scholar
  46. [54]54. Crews, L. ∙ Spencer, B. ∙ Desplats, P. ... Selective molecular alterations in the autophagy pathway in patients with Lewy body disease and in models of α-synucleinopathy PLoS ONE. 2010; 5:e9313 Crossref Scopus (323) PubMed Google Scholar
  47. [55]55. Lafay-Chebassier, C. ∙ Pérault-Pochat, M.C. ∙ Page, G. ... The immunosuppressant rapamycin exacerbates neurotoxicity of Aβ peptide J. Neurosci. Res. 2006; 84:1323-1334 Crossref Scopus (55) PubMed Google Scholar
  48. [56]56. Hung, S.Y. ∙ Huang, W.P. ∙ Liou, H.C. ... Autophagy protects neuron from Aβ-induced cytotoxicity Autophagy. 2009; 5:502-510 Crossref Scopus (173) PubMed Google Scholar
  49. [57]57. Ling, D. ∙ Song, H.J. ∙ Garza, D. ... Aβ42-induced neurodegeneration via an age-dependent autophagic-lysosomal injury in Drosophila PLoS ONE. 2009; 4:e4201 Crossref Scopus (149) PubMed Google Scholar
  50. [59]59. Caccamo, A. ∙ Majumder, S. ∙ Richardson, A. ... Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-β, and τ: effects on cognitive impairments J. Biol. Chem. 2010; 285:13107-13120 Full Text Full Text (PDF) Scopus (758) PubMed Google Scholar
  51. [60]60. Majumder, S. ∙ Richardson, A. ∙ Strong, R. ... Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits PLoS ONE. 2011; 6:e25416 Crossref Scopus (342) PubMed Google Scholar
  52. [61]61. Caccamo, A. ∙ De Pinto, V. ∙ Messina, A. ... Genetic reduction of mammalian target of rapamycin ameliorates Alzheimer’s disease-like cognitive and pathological deficits by restoring hippocampal gene expression signature J. Neurosci. 2014; 34:7988-7998 Crossref Scopus (152) PubMed Google Scholar
  53. [62]62. Mucke, L. ∙ Masliah, E. ∙ Yu, G.Q. ... High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation J. Neurosci. 2000; 20:4050-4058 Crossref PubMed Google Scholar
  54. [63]63. Zhou, B. ∙ Cai, Q. ∙ Xie, Y. ... Snapin recruits dynein to BDNF-TrkB signaling endosomes for retrograde axonal transport and is essential for dendrite growth of cortical neurons Cell Rep. 2012; 2:42-51 Full Text Full Text (PDF) Scopus (108) PubMed Google Scholar
  55. [64]64. Cai, Q. ∙ Zakaria, H.M. ∙ Simone, A. ... Spatial parkin translocation and degradation of damaged mitochondria via mitophagy in live cortical neurons Curr. Biol. 2012; 22:545-552 Full Text Full Text (PDF) Scopus (273) PubMed Google Scholar
  56. [65]65. Goslin, K. ∙ Banker, G. Rat hippocampal neurons in low-density culture Culturing Nerve Cells. 1998; 2:339-370 Google Scholar
  57. [66]66. Nagahara, A.H. ∙ Mateling, M. ∙ Kovacs, I. ... Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice J. Neurosci. 2013; 33:15596-15602 Crossref Scopus (140) PubMed Google Scholar
  58. [67]67. Kang, J.S. ∙ Tian, J.H. ∙ Pan, P.Y. ... Docking of axonal mitochondria by syntaphilin controls their mobility and affects short-term facilitation Cell. 2008; 132:137-148 Full Text Full Text (PDF) Scopus (460) PubMed Google Scholar
  59. [68]68. Banker, G.A. ∙ Cowan, W.M. Further observations on hippocampal neurons in dispersed cell culture J. Comp. Neurol. 1979; 187:469-493 Crossref Scopus (226) PubMed Google Scholar
  60. [69]69. Miller, K.E. ∙ Sheetz, M.P. Axonal mitochondrial transport and potential are correlated J. Cell Sci. 2004; 117:2791-2804 Crossref Scopus (435) PubMed Google Scholar Figures (8) Article metrics Related Articles Advertisement Hide CaptionDownloadSee figure in Article Toggle Thumbstrip FIGURE 1 FIGURE 2 FIGURE 3 FIGURE 4 FIGURE 5 FIGURE 6 FIGURE 7 FIGURE 8 Download .PPT Home Access for Developing Countries Articles Papers in Press Current Volume Archive Editorials ASBMB Award Articles JBC Reviews Meeting Reports Thematic Series Virtual Issues Classics Reflections Editors' Picks JBC Communications eLetters Tabor Awards For Authors Information for Authors About Open Access Permissions Submit manuscript Submission Help Contact Us Contact Information Journal Info About the Journal Early Career Reviewers Editorial Board Image Gallery New Content Alerts All Topics Bioenergetics Cell Biology Computational Biology Developmental Biology DNA and Chromosomes Enzymology Gene Regulation Genomics and Proteomics Glycobiology and Extracellular Matrices Immunology Lipids Membrane Biology Metabolism

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Authors
Feng, T., Tammineni, P., Agrawal, C., Jeong, Y. Y., & Cai, Q.
Affiliations
Rutgers, The State University of New Jersey (US)
Corresponding author
Cai, Qian
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2017-02
Volume
292
Issue
5
Pages
1679-1690
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m116.766584
PMC
PMC5290944
OpenAlex
W2565530803
Cited by
69
References
9
Citations by year
2026: 8 · 2025: 3 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 12 · 2020: 13 · 2019: 9 · 2018: 7 · 2017: 2
FWCI
4.11
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Rutgers University Community Repository (Rutgers University) (submittedVersion)
Funders
  • National Institutes of Health (R00AG033658, R01NS089737)
  • Alzheimer's Association (NIRG-14-321833)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
BACE1, autophagy, autophagy-lysosome pathway, protein trafficking, axonal transport, retrograde transport, Snapin, lysosomal degradation, amyloid-beta production, APP processing, Alzheimer's disease, distal axons, autophagosomes
MeSH terms
Alzheimer Disease, Animals, Autophagy, Axons, Brain, Disease Models, Animal, Lysosomes, Mice, Transgenic, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, Vesicular Transport Proteins, Mice, Amyloid Precursor Protein Secretases, Proteolysis

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