Intracellular Itinerary of Internalised β‐Secretase, BACE1, and Its Potential Impact on β‐Amyloid Peptide Biogenesis
Abstract
β‐Secretase (BACE1) cleavage of the amyloid precursor protein (APP) represents the initial step in the formation of the Alzheimer's disease associated amyloidogenic Aβ peptide. Substantive evidence indicates that APP processing by BACE1 is dependent on intracellular sorting of this enzyme. Nonetheless, knowledge of the intracellular trafficking pathway of internalised BACE1 remains in doubt. Here we show that cell surface BACE1 is rapidly internalised by the AP2/clathrin dependent pathway in transfected cells and traffics to early endosomes and Rab11‐positive, juxtanuclear recycling endosomes, with very little transported to the TGN as has been previously suggested. Moreover, BACE1 is predominantly localised to the early and recycling endosome compartments in different cell types, including neuronal cells. In contrast, the majority of internalised wild‐type APP traffics to late endosomes/lysosomes. To explore the relevance of the itinerary of BACE1 on APP processing, we generated a BACE1 chimera containing the cytoplasmic tail of TGN38 (BACE/TGN38), which cycles between the cell surface and TGN in an AP2‐dependent manner. Wild‐type BACE1 is less efficient in Aβ production than the BACE/TGN38 chimera, highlighting the relevance of the itinerary of BACE1 on APP processing. Overall the data suggests that internalised BACE1 and APP diverge at early endosomes and that Aβ biogenesis is regulated in part by the recycling itinerary of BACE1.
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Internalized BACE1 traffics to early endosomes and recycles back to the plasma membrane via recycling endosomes.
“The intracellular itinerary of internalized BACE1 to the early endosomes followed by the recycling of BACE1 back to the plasma membrane (PM) via the recycling endosomes has been established previously (Chia et al., 2013; Toh et al., 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 Chia et al., 2013
Redirecting the BACE1 plasma membrane recycling pathway via the TGN using a chimeric BACE1/TGN38 construct leads to increased Aβ production.
“redirecting the BACE1 plasma membrane recycling pathway via the trans-Golgi network (TGN), using a chimeric BACE1/TGN38 construct (TGN38 is known to traffic from the endosomes to the TGN), leads to increased Aβ production (Chia et al., 2013).”
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 Chia et al., 2013
The distribution of BACE1-GFP is very similar to the steady-state distribution of transiently expressed untagged BACE1 in HeLa cells and to the distribution of BACE1-SBP-GFP in the RUSH system in the continuous presence of biotin.
“This distribution of BACE1-GFP is very similar to the steady-state distribution of transiently expressed untagged BACE1 in HeLa cells (Chia et al., 2013) and to the distribution of BACE1-SBP-GFP in the RUSH system in the continuous presence of biotin (Table 1).”
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 Chia et al., 2013
Arrival of BACE1 at early and recycling endosomes at 30 min most likely represents internalized BACE1 from the PM.
“Arrival of BACE1 at the early and recycling endosomes at the 30-min time point most likely represents internalized BACE1 from the PM (Chia et al., 2013).”
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 Chia et al., 2013
The intracellular distribution of BACE1-SBP-GFP at an extended time point was very similar to steady-state distribution of BACE1 in stable or transiently transfected HeLa cells, with or without GFP tag, indicating SBP and GFP tags are unlikely to interfere with BACE1-SBP-GFP trafficking in RUSH.
“The intracellular distribution of BACE1-SBP-GFP at an extended time point was very similar to the steady-state distribution of BACE1 in either stable or transiently transfected HeLa cells, with or without a GFP tag (Chia et al., 2013), indicating that the SBP and GFP tags are unlikely to interfere with the trafficking of BACE1-SBP-GFP in the RUSH system.”
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 Chia et al., 2013
Enhanced APP cleavage was detected at TGN upon redirection of BACE1 recycling to this compartment using BACE1/TGN38 chimera.
“our earlier study where enhanced APP cleavage was detected at the TGN upon the redirection of BACE1 recycling to this compartment using a BACE1/TGN38 chimera (Chia et al., 2013).”
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 Chia et al., 2013
The current studies involved silencing in a stable cell line expressing only modest levels of BACE1-GFP, to minimize possibility of saturation of post-Golgi transport machinery.
“The current studies involved silencing of trafficking machinery in a stable cell line expressing only modest levels of BACE1-GFP, to minimize the possibility of saturation of the post-Golgi transport machinery (Chia et al., 2013).”
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 Chia et al., 2013
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
Self-citationMuhammad, 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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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-citation
- Authors
- Chia, P. Z. C., Toh, W. H., Sharples, R., Gasnereau, I., Hill, A. F., & Gleeson, P. A.
- Affiliations
- The University of Melbourne (AU)
- Mental Health Research Institute (AU)
- Corresponding author
- Gleeson, Paul A.
- Venue
- Traffic
- Publisher
- Wiley
- Published
- 2013-07-08
- Volume
- 14
- Issue
- 9
- Pages
- 997-1013
- ISSN
- 1398-9219 (ISSN-L)
- 1600-0854
- OpenAlex
- W1949229324
- Cited by
- 67
- References
- 2
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 2 · 2022: 5 · 2021: 9 · 2020: 10 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 7 · 2015: 6 · 2014: 6 · 2013: 1
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Traffic (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Victoria University Research Repository (Victoria University) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- 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, beta-secretase, amyloid precursor protein, early endosomes, recycling endosomes, Rab11, TGN38, trans-Golgi network, Alzheimer's disease, APP processing, neurons
- MeSH terms
- Animals, Cell Line, Cell Membrane, Clathrin, Cricetulus, Cytoplasm, HeLa Cells, Humans, Lysosomes, Endosomes, Amyloid beta-Peptides, CHO Cells, Protein Transport, Cell Line, Tumor, Amyloid Precursor Protein Secretases, RNA, Long Noncoding
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