BACE1 activity is modulated by cell-associated sphingosine-1-phosphate
Open accessAbstract
Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease.
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SphK2/S1P signaling is a potential target for multitargeted therapy, that is, Aβ production in neurons and Aβ metabolism via the regulation of ApoE expression in astrocytes.
“SphK2/S1P signaling is a potential target for multitargeted therapy, that is, Aβ production in neurons and Aβ metabolism via the regulation of ApoE expression in astrocytes”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [17]
The Results and Discussion support SphK2/S1P as a potential Alzheimer’s therapeutic target through its effect on neuronal Aβ production. They do not address Aβ metabolism through regulation of ApoE expression in astrocytes, so the proposed multitargeted mechanism is not fully supported. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredS1P is involved in Aβ production in neurons.
“we have previously shown to be involved in Aβ production in neurons (17)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [17]
The SphK2/S1P pathway is activated in AD pathology.
“Here, we focused on the SphK2/S1P pathway, a lipid signaling pathway, which we previously showed to be activated in AD pathology (17).”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [17]
SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons.
“Considering our previous findings that SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [17]
SphK2 activity is increased in the frontal cortex of AD brains.
“We have shown an increase in SphK2 activity in the frontal cortex of AD brains (17)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [17]
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Cites
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“However, modest reduction of BACE1 activity is sufficient for a significant reduction in brain A deposition in AD model mice (McConlogue et al., 2007; Chow et al., 2010).”
BackgroundSavonenko, A. V., Melnikova, T., Laird, F. M., Stewart, K.-A., Price, D. L., & Wong, P. C. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0710373105 · Cited by 290 · see citing works
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Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes
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Self-citation
- Authors
- Takasugi, N., Sasaki, T., Suzuki, K., Osawa, S., Isshiki, H., Hori, Y., Shimada, N., Higo, T., Yokoshima, S., Fukuyama, T., Lee, V. M.-Y., Trojanowski, J. Q., Tomita, T., & Iwatsubo, T.
- Affiliations
- The University of Tokyo (JP)
- University of Pennsylvania (US)
- Japan Science and Technology Agency (JP)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2011-05-04
- Volume
- 31
- Issue
- 18
- Pages
- 6850-6857
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC4534000
- OpenAlex
- W2041029999
- Cited by
- 181
- References
- 6
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 8 · 2023: 10 · 2022: 4 · 2021: 17 · 2020: 13 · 2019: 10 · 2018: 19 · 2017: 20 · 2016: 16 · 2015: 5 · 2014: 18 · 2013: 11 · 2012: 14
- FWCI
- 10.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Chicago
- Japan Science and Technology Corporation
- National Institute of Biomedical Innovation
- National Institutes of Health (AG 10 124)
- Japan Society for the Promotion of Science
- National Institute on Aging (P30AG010124, AG-10124)
- Core Research for Evolutional Science and Technology
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- BACE1, sphingosine-1-phosphate, sphingosine kinase, amyloid-beta production, Alzheimer's disease, sphingosine kinase 2, neurons, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Cells, Cultured, Cerebral Cortex, Humans, Lysophospholipids, Neurons, Sphingosine, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, RNA Interference, Mice, Amyloid Precursor Protein Secretases
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