Sorting Nexin 27 Regulates Aβ Production through Modulating γ-Secretase Activity
Open accessAbstract
Patients with Down syndrome (DS) invariably develop Alzheimer's disease (AD) pathology in their 40s. We have recently found that overexpression of a chromosome 21-encoded microRNA-155 results in decreased levels of the membrane trafficking component, SNX27, diminishing glutamate receptor recycling and thereby impairing synaptic functions in DS. Here, we report a function of SNX27 in regulating β-amyloid (Aβ) generation by modulating γ-secretase activity. Downregulation of SNX27 using RNAi increased Aβ production, whereas overexpression of full-length SNX27, but not SNX27ΔPDZ, reversed the RNAi-mediated Aβ elevation. Moreover, genetic deletion of Snx27 promoted Aβ production and neuronal loss, whereas overexpression of SNX27 using an adeno-associated viral (AAV) vector reduced hippocampal Aβ levels in a transgenic AD mouse model. SNX27 associates with the γ-secretase complex subunit presenilin 1; this interaction dissociates the γ-secretase complex, thus decreasing its proteolytic activity. Our study establishes a molecular mechanism for Aβ-dependent pathogenesis in both DS and AD.
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SNX27 limits Aβ production through interaction with PS1 destabilizing the γ-secretase complex, and enhances non-amyloidogenic APP processing by promoting APP recycling via SORLA.
“SNX27 regulates APP processing via two pathways: SNX27 can limit Aβ production through the interaction with PS1 which leads to destabilization of γ-secretase complex; in addition, SNX27 can enhance non-amyloidogenic APP processing through promoting the recycling of APP to the cell surface via interacting with SORLA [47, 48].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [48]
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References 56 · Cited by 77
- Authors
- Wang, X., Huang, T., Zhao, Y., Zheng, Q., Thompson, R. C., Bu, G., Zhang, Y.-W., Hong, W., & Xu, H.
- Affiliations
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Xiamen University (CN)
- Corresponding author
- Xu, Huaxi
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 9
- Issue
- 3
- Pages
- 1023-1033
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4328673
- OpenAlex
- W1991466748
- Cited by
- 77
- References
- 56
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 12 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 7 · 2019: 5 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 6 · 2014: 1
- FWCI
- 5.56
- 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)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institute on Aging (P01AG030128, R01AG044420, R01AG038710, R01AG027924, R01AG030197, R01AG021173, RF1AG046205, R21AG049247)
- National Institute of Neurological Disorders and Stroke (R01NS046673, P01NS074969)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- SNX27, amyloid-beta production, gamma-secretase, presenilin 1, Down syndrome, Alzheimer's disease, chromosome 21, miR-155, PDZ domain, neuronal loss, hippocampus, adeno-associated virus vectors
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, HeLa Cells, Humans, Mice, Transgenic, Models, Biological, Neurons, Protein Binding, Amyloid beta-Peptides, Gene Deletion, Protein Subunits, Receptors, Notch, Presenilin-1, Amyloid Precursor Protein Secretases, HEK293 Cells, Sorting Nexins
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