The X11α protein slows cellular amyloid precursor protein processing and reduces Aβ40 and Aβ42 secretion
Open accessAbstract
Constitutive amyloid precursor protein (APP) metabolism results in the generation of soluble APP (APPs) and Abeta peptides, including Abeta40 and Abeta42-the major component of amyloid plaques in Alzheimer's disease brain. The phosphotyrosine binding (PTB) domain of X11 binds to a peptide containing a YENPTY motif found in the carboxyl terminus of APP. We have cloned the full-length X11 gene now referred to as X11alpha. Coexpression of X11alpha with APP results in comparatively greater levels of cellular APP and less APPs, Abeta40, and Abeta42 recovered in conditioned medium of transiently transfected HEK 293 cells. These effects are impaired by a single missense mutation of either APP (Y682G within the YENPTY motif) or X11alpha (F608V within the PTB domain), which diminishes their interaction, thus demonstrating specificity. The inhibitory effect of X11alpha on Abeta40 and Abeta42 secretion is amplified by coexpression with the Swedish mutation of APP (K595N/M596L), which promotes its amyloidogenic processing. Pulse-chase analysis demonstrates that X11alpha prolongs the half-life of APP from approximately 2 h to approximately 4 h. The effects of X11alpha on cellular APP and APPs recovery were confirmed in a 293 cell line stably transfected with APP. The specific binding of the PTB domain of X11alpha to the YENPTY motif-containing peptide of APP appears to slow cellular APP processing and thus reduces recovery of its soluble fragments APPs, Abeta40, and Abeta42 in conditioned medium of transfected HEK 293 cells. X11alpha may be involved in APP trafficking and metabolism in neurons and thus may be implicated in amyloidogenesis in normal aging and Alzheimer's disease brain.
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The half-life of APP695 in control HEK 293 cells is 2.6 h.
“The half life of APP695 in control 293 cells was 2.6 h, a value that is consistent with prior studies (Borg et al., 1998).”
From LRAD3, A Novel Low-Density Lipoprotein Receptor Family Member That Modulates Amyloid Precursor Protein Trafficking (2011) · cites this paper as Borg et al., 1998
The X11α Coexpression section reports an APP half-life of approximately 2 hours in HEK 293 cells, and the Experimental Procedures specify that the study used APP695. This supports a similar control-cell half-life, but the source does not report the cited value of 2.6 hours. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAPP and ApoER2 bind the adaptor proteins X11α/β, Fe65, Snx17, Dab1, and Dab2, and these interactions regulate their surface expression and processing.
“Intracellularly, APP and ApoER2 bind the adaptor proteins X11␣/ (67-70), Fe65 (69, 71, 72), Snx17 (73, 74), Dab1 (75-79), and Dab2 (73, 80), and these interactions regulate their surface expression and processing (Fig. 4).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [70]
Surface localization of APP and ApoER2 and non-amyloidogenic processing of APP are altered by intracellular interactions with X11α/β.
“X11␣/ (right panel) (67-70).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [70]
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“The half-life of APP695 in control HEK 293 cells was 2.6 h, a value that is consistent with previous studies (Borg et al., 1998).”
MethodResultInfluential
- Authors
- Borg, J.-P., Yang, Y., De Taddéo-Borg, M., Margolis, B., & Turner, R. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Michigan (US)
- Corresponding author
- Turner, R. Scott
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1998-06
- Volume
- 273
- Issue
- 24
- Pages
- 14761-14766
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1994346902
- Cited by
- 201
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 2 · 2019: 4 · 2018: 1 · 2017: 3 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 10
- FWCI
- 10.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (P50AG008671, P50 AG08671)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid precursor protein, APP processing, amyloid-beta secretion, Aβ40, amyloid-beta 42, phosphotyrosine binding domain, APP trafficking, Swedish mutation, Alzheimer's disease, amyloidogenesis, soluble APP
- MeSH terms
- Alzheimer Disease, Binding Sites, Cell Line, Cloning, Molecular, Humans, Kidney, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Endopeptidases, Protein Processing, Post-Translational, Gene Expression, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Culture Media, Conditioned, Sequence Analysis, DNA, Phosphotyrosine, Amyloid Precursor Protein Secretases
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