Snapin-Mediated BACE1 Retrograde Transport Is Essential for Its Degradation in Lysosomes and Regulation of APP Processing in Neurons
Open accessAbstract
β site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is the major β secretase for generating β-amyloid (Aβ) peptides. The acidic environment of endosomes is optimal for β secretase activity. However, the mechanisms regulating BACE1 traffic from endosomes to lysosomes for degradation are largely unknown. Here, using snapin-deficient mice combined with gene rescue experiments, we reveal that Snapin, as a dynein motor adaptor for late endosomes, mediates BACE1 retrograde transport. hAPP mutant live neurons and mouse brains exhibited BACE1 accumulation within the altered late endocytic organelles and defective lysosomal targeting due to reduced Snapin-dynein coupling. Deleting snapin or disrupting Snapin-dynein coupling reduces BACE1 transport to lysosomes for degradation, thus enhancing APP processing. Overexpressing Snapin in hAPP neurons reduces β site cleavage of APP by enhancing BACE1 turnover. Altogether, our study provides mechanistic insights into the complex regulation of BACE1 level and activity and turnover through retrograde transport, thus controlling Aβ generation in neurons.
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Synaptic protein snapin, an EHD1-binding protein, was identified as a regulator of endosome-to-lysosome retrograde transport of BACE1.
“Recently, the synaptic protein snapin, which is an EHD1-binding protein, was identified as a regulator of the endosome-to-lysosome retrograde transport of BACE1 (27,45).”
From BIN1 regulates BACE1 intracellular trafficking and amyloid-β production (2016) · cites this paper as [27]
The Discussion states that Snapin-mediated retrograde transport delivers BACE1 from late endosomes to somatic lysosomes for degradation. The Results also show impaired BACE1 retrograde transport in snapin-deficient neurons. Our copy does not identify Snapin as an EHD1-binding protein (searched: “EHD1-binding protein snapin” and “EHD1”), so that descriptor is not supported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe presence of BACE1-SBP-GFP in late endosomes/lysosomes suggests turnover of BACE1 in the lysosomes.
“suggesting turnover of BACE1 in the lysosomes (Ye and Cai, 2014; Ye et al., 2017; Feng 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 Ye and Cai, 2014
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Cites
Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain
Takahashi, R. H., Almeida, C. G., Kearney, P. F., Yu, F., Lin, M. T., Milner, T. A., & Gouras, G. K. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5167-03.2004 · Cited by 445 · see citing works
β-Secretase Activity Increases with Aging in Human, Monkey, and Mouse Brain
Fukumoto, H., Rosene, D. L., Moss, M. B., Raju, S., Hyman, B. T., & Irizarry, M. C. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63159-8 · Cited by 294 · see citing works
Jankowsky, J. L., Slunt, H. H., Gonzales, V., Savonenko, A. V., Wen, J. C., Jenkins, N. A., Copeland, N. G., Younkin, L. H., Lester, H. A., Younkin, S. G., et al. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020355 · Cited by 237 · see citing works
Kang, E. L., Biscaro, B., Piazza, F., & Tesco, G. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.407072 · Cited by 55 · see citing works
Flagged first, then by citations
Research works printed but not linked: 23
- Cai H Wang Y McCarthy D Wen H Borchelt DR Price DL Wong PC BACE1 is the major beta-secretase for generation of Abeta peptides by neurons Nat Neurosci 2001 4 233 234 11224536
- Cai Q Lu L Tian JH Zhu YB Qiao H Sheng ZH Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons Neuron 2010 68 73 86 20920792 PMC2953270
- Das U Scott DA Ganguly A Koo EH Tang Y Roy S Activity-induced convergence of APP and BACE-1 in acidic microdomains via an endocytosis-dependent pathway Neuron 2013 79 447 460 23931995 PMC3741682
- Ginsberg SD Mufson EJ Counts SE Wuu J Alldred MJ Nixon RA Che S Regional selectivity of rab5 and rab7 protein upregulation in mild cognitive impairment and Alzheimer's disease J Alzheimers Dis 2010 22 631 639 20847427 PMC3031860
- Haass C Koo EH Mellon A Hung AY Selkoe DJ Targeting of cell-surface beta-amyloid precursor protein to lysosomes: alternative processing into amyloid-bearing fragments Nature 1992 357 500 503 1608449
- Hardy J Selkoe DJ The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics Science 2002 297 353 356 12130773
- Huse JT Pijak DS Leslie GJ Lee VM Doms RW Maturation and endosomal targeting of beta-site amyloid precursor protein-cleaving enzyme. The Alzheimer's disease beta-secretase J Biol Chem 2000 275 33729 33737 10924510
- Koo EH Squazzo SL Evidence that production and release of amyloid beta-protein involves the endocytic pathway J Biol Chem 1994 269 17386 17389 8021238
- Lee S Sato Y Nixon RA Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy J Neurosci 2011 31 7817 7830 21613495 PMC3351137
- Lefort R Pozueta J Shelanski M Cross-linking of cell surface amyloid precursor protein leads to increased beta-amyloid peptide production in hippocampal neurons: implications for Alzheimer's disease J Neurosci 2012 32 10674 10685 22855816 PMC3539764
- Mucke L Masliah E Yu GQ Mallory M Rockenstein EM Tatsuno G Hu K Kholodenko D Johnson-Wood K McConlogue L High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation J Neurosci 2000 20 4050 4058 10818140 PMC6772621
- Nixon RA Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases Neurobiol Aging 2005 26 373 382 15639316
- Poon WW Carlos AJ Aguilar BL Berchtold NC Kawano CK Zograbyan V Yaopruke T Shelanski M Cotman CW beta-Amyloid (Abeta) Oligomers Impair Brain-derived Neurotrophic Factor Retrograde Trafficking by Down-regulating Ubiquitin C-terminal Hydrolase, UCH-L1 J Biol Chem 2013 288 16937 16948 23599427 PMC3675626
- Prabhu Y Burgos PV Schindler C Farias GG Magadan JG Bonifacino JS Adaptor protein 2-mediated endocytosis of the beta-secretase BACE1 is dispensable for amyloid precursor protein processing Mol Biol Cell 2012 23 2339 2351 22553349 PMC3374752
- Sannerud R Declerck I Peric A Raemaekers T Menendez G Zhou L Veerle B Coen K Munck S De Strooper B 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 568 21825135 PMC3161548
- Stokin GB Goldstein LS Axonal transport and Alzheimer's disease Annu Rev Biochem 2006 75 607 627 16756504
- Takahashi RH Milner TA Li F Nam EE Edgar MA Yamaguchi H Beal MF Xu H Greengard P Gouras GK Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology Am J Pathol 2002 161 1869 1879 12414533 PMC1850783
- Tesco G Koh YH Kang EL Cameron AN Das S Sena-Esteves M Hiltunen M Yang SH Zhong Z Shen Y Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity Neuron 2007 54 721 737 17553422 PMC1973166
- Vassar R Kovacs DM Yan R Wong PC The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential J Neurosci 2009 29 12787 12794 19828790 PMC2879048
- Wang CL Tang FL Peng Y Shen CY Mei L Xiong WC VPS35 regulates developing mouse hippocampal neuronal morphogenesis by promoting retrograde trafficking of BACE1 Biol Open 2012 1 1248 1257 23259059 PMC3522886
- Wu J Petralia RS Kurushima H Patel H Jung MY Volk L Chowdhury S Shepherd JD Dehoff M Li Y Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent beta-amyloid generation Cell 2011 147 615 628 22036569 PMC3207263
- Yang LB Lindholm K Yan R Citron M Xia W Yang XL Beach T Sue L Wong P Price D Elevated beta-secretase expression and enzymatic activity detected in sporadic Alzheimer disease Nat Med 2003 9 3 4 12514700
- Zhou B Cai Q Xie Y Sheng ZH 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 22840395 PMC3408618
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Sorted by citations
Myelin dysfunction drives amyloid-β deposition in models of Alzheimer’s disease
Depp, C., Sun, T., Sasmita, A. O., Spieth, L., Berghoff, S. A., Nazarenko, T., Overhoff, K., Steixner-Kumar, A. A., Subramanian, S., Arinrad, S., et al. (2023) · Nature · doi:10.1038/s41586-023-06120-6 · Cited by 476 · see citing works
Gowrishankar, S., Yuan, P., Wu, Y., Schrag, M., Paradise, S., Grutzendler, J., De Camilli, P., & Ferguson, S. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510329112 · Cited by 406 · see citing works
BIN1 regulates BACE1 intracellular trafficking and amyloid-β production
Miyagawa, T., Ebinuma, I., Morohashi, Y., Hori, Y., Young Chang, M., Hattori, H., Maehara, T., Yokoshima, S., Fukuyama, T., Tsuji, S., et al. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddw146 · Cited by 95 · see citing works
Adenylate cyclase-centred microdomains
Cooper, D. M. F., & Tabbasum, V. G. (2014) · Biochemical Journal · doi:10.1042/bj20140560 · Cited by 68 · see citing works
BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer’s disease
Bao, J., Qin, M., Mahaman, Y. A. R., Zhang, B., Huang, F., Zeng, K., Xia, Y., Ke, D., Wang, Q., Liu, R., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1800498115 · Cited by 50 · see citing works
Vijayan, M., Alvir, R. V., Alvir, R. V., Bunquin, L. E., Pradeepkiran, J. A., & Reddy, P. H. (2022) · Aging Cell · doi:10.1111/acel.13663 · Cited by 40 · 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
- Authors
- Ye, X., & Cai, Q.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Corresponding author
- Cai, Qian
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-01
- Volume
- 6
- Issue
- 1
- Pages
- 24-31
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3905048
- OpenAlex
- W2042508628
- Cited by
- 63
- References
- 4
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 7 · 2020: 3 · 2019: 6 · 2018: 7 · 2017: 8 · 2016: 3 · 2015: 6 · 2014: 4
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health
- National Institute on Aging (R00AG033658)
- National Institute of Neurological Disorders and Stroke (R01NS089737)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- BACE1, Snapin, retrograde transport, lysosomal degradation, dynein motor, late endosomes, APP processing, amyloid-beta, endosomal trafficking, Alzheimer's disease
- MeSH terms
- Animals, Dyneins, Lysosomes, Neurons, Endosomes, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Gene Deletion, Protein Transport, Vesicular Transport Proteins, Mice, Amyloid Precursor Protein Secretases, Proteolysis
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