Proteomic identification of sorting nexin 6 as a negative regulator of BACE1‐mediated APP processing
Open accessAbstract
The β‐site APP cleaving enzyme‐1 (BACE1) mediates the first cleavage of the β‐amyloid precursor protein (APP) to yield the amyloid β‐peptide (Aβ), a key pathogenic agent in Alzheimer's disease (AD). Using a proteomic approach based on in‐cell chemical cross‐linking and tandem affinity purification (TAP), we herein identify sorting nexin 6 (SNX6) as a BACE1‐associated protein. SNX6, a PX domain protein, is a putative component of retromer, a multiprotein cargo complex that mediates the retrograde trafficking of the cation‐independent mannose‐6‐phosphate receptor (CI‐MPR) and sortilin. RNA interference suppression of SNX6 increased BACE1‐dependent secretion of soluble APP (sAPPβ) and cell‐associated fragments (C99), resulting in increased Aβ secretion. Furthermore, SNX6 reduction led to elevated steady‐state BACE1 levels as well as increased retrograde transport of BACE1 in the endocytic pathway, suggesting that SNX6 modulates the retrograde trafficking and basal levels of BACE1, thereby regulating BACE1‐mediated APP processing and Aβ biogenesis. Our study identifies a novel cellular pathway by which SNX6 negatively modulates BACE1‐mediated cleavage of APP.—Okada, H., Zhang, W., Peterhoff, C., Hwang, J. C., Nixon, R. A., Ryu, S. H., Kim, T.‐W. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1‐mediated APP processing. FASEB J . 24, 2783–2794 (2010). www.fasebj.org
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SNX6 associates with BACE1, and reducing SNX6 levels increases Aβ generation.
“For instance, SNX6 can associate with BACE1 and reducing SNX6 levels results in elevated steady-state BACE1 levels as well as increased endocytic retrograde BACE1 transport, thus increasing Aβ generation [45].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [45]
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- Authors
- Okada, H., Zhang, W., Peterhoff, C., Hwang, J. C., Nixon, R. A., Ryu, S. H., & Kim, T.
- Affiliations
- Columbia University Irving Medical Center (US)
- Nathan Kline Institute for Psychiatric Research (US)
- Pohang University of Science and Technology (KR)
- Corresponding author
- Kim, Tae‐Wan
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2010-03-30
- Volume
- 24
- Issue
- 8
- Pages
- 2783-2794
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC2909280
- OpenAlex
- W2165318026
- Cited by
- 102
- References
- 49
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 9 · 2017: 6 · 2016: 9 · 2015: 9 · 2014: 6 · 2013: 5 · 2012: 8
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Funders
- Alzheimer's Disease Research Foundation
- National Institutes of Health (AG‐09702)
- American Health Assistance Foundation
- 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 › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- BACE1, APP processing, amyloid-beta, Alzheimer's disease, retromer complex, retrograde trafficking, endocytic pathway, PX domain, tandem affinity purification
- MeSH terms
- Carrier Proteins, Cell Line, Humans, Hydrolysis, Solubility, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, Vesicular Transport Proteins, Proteomics, Amyloid Precursor Protein Secretases, Sorting Nexins
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