Binding of F-spondin to amyloid-β precursor protein: a candidate amyloid-β precursor protein ligand that modulates amyloid-β precursor protein cleavage
Open accessAbstract
Amyloid-β precursor protein (APP), a type I membrane protein, is physiologically processed by α- or β-secretases that cleave APP N-terminal to the transmembrane region. Extracellular α-/β-cleavage of APP generates a large secreted N-terminal fragment, and a smaller cellular C-terminal fragment. Subsequent γ-secretase cleavage in the transmembrane region of the C-terminal fragment induces secretion of small extracellular peptides, including Aβ 40 and Aβ 42 , which are instrumental in the pathogenesis of Alzheimer's disease, and intracellular release of a cytoplasmic tail fragment. Although APP resembles a cell-surface receptor, no functionally active extracellular ligand for APP that might regulate its proteolytic processing has been described. We now show that F-spondin, a secreted signaling molecule implicated in neuronal development and repair, binds to the conserved central extracellular domain of APP and inhibits β-secretase cleavage of APP. Our data indicate that F-spondin may be an endogenous regulator of APP cleavage, and suggest that the extracellular domains of APP are potential drug targets for interfering with β-secretase cleavage.
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F-spondin may function as a linker between ApoER2 and APP through its interaction with extracellular and intracellular domains of APP.
“F-spondin may function as a linker between ApoER2 and APP through its interaction with extracellular and intracellular domains of APP (Ho and Sudhof, 2004).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Ho and Sudhof, 2004
The Results (page unavailable) show that F-spondin binds the extracellular central domain of APP. The Discussion (page unavailable) identifies APP and APLPs as its binding partners, but does not describe an ApoER2–APP link or binding to an intracellular APP domain. (LLM, conf=0.88)
Experimental — accuracy not yet measuredF-spondin binds both ApoER2 and APP, enhances their surface expression, and reduces Aβ formation.
“The extracellular ligand, F-spondin, binds both ApoER2 and APP, enhances their surface expression, and reduces A formation (65,66).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [65]
ApoER2 binds thrombospondin repeats 1-4 of F-spondin, whereas APP binds the Reelin and Spondin domain of F-spondin.
“ApoER2 binds the thrombospondin repeats 1-4 (pink triangles) of F-spondin, whereas APP binds the Reelin and Spondin domain of F-spondin (65, 66).”
From Reelin: Neurodevelopmental Architect and Homeostatic Regulator of Excitatory Synapses (2017) · cites this paper as [65]
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- Authors
- Ho, A., & Südhof, T. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- ORCID
- Südhof, Thomas C.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-02-17
- Volume
- 101
- Issue
- 8
- Pages
- 2548-2553
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC356987
- OpenAlex
- W1971856927
- Cited by
- 224
- References
- 43
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 4 · 2018: 10 · 2017: 10 · 2016: 17 · 2015: 11 · 2014: 8 · 2013: 15 · 2012: 11
- FWCI
- 8.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (F32AG005844, AG05844)
- National Institute of Mental Health (R01MH069585, R01-MH59686-01)
- 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
- F-spondin, amyloid precursor protein, APP cleavage, beta-secretase inhibition, amyloid-beta, Alzheimer's disease, gamma-secretase, therapeutic target
- MeSH terms
- Animals, Brain, Cell Line, Chromatography, Affinity, Humans, Hydrolysis, Kinetics, Ligands, Peptides, Recombinant Fusion Proteins, Transfection, Extracellular Matrix Proteins, Amyloid beta-Protein Precursor, Intercellular Signaling Peptides and Proteins, Rats
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