Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment
Open accessAbstract
Significance: Cognitive function decreases during aging, but the mechanisms involved remain unclear. Revolutionary recent studies revealed that introduction of blood from young mice into old mice increased cognitive abilities and synaptic connectivity, suggesting that young blood contains specific factors supporting cognitive function. Here, we asked whether young blood is enriched in factors that act directly on neurons to promote synapse formation. We show that serum from young but not old mice indeed directly boosts synapse formation in cultured neurons, and identify two factors, thrombospondin-4 and SPARCL1, that are enriched in young blood and mediate these effects. Thus, our experiments show that young blood is enriched in multiple factors that directly promote synaptic connectivity between neurons.
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In in vitro experiments, thrombospondin-4 and SPARC-like protein 1 act directly on neurons to stimulate synapse formation and enhance synaptic responses.
“In in vitro experiments, thrombospondin-4 (THBS4) and SPARC-like protein 1 (SPARCL1) act directly on neurons to stimulate synapse formation and enhance synaptic responses.387”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [387]
Proteomic and functional validation experiments suggest that the young blood effect is at least partly mediated by SPARC1L and thrombospondin-4.
“Proteomic and functional validation experiments suggest that the effect is at least partly mediated by SPARC1L and thrombospondin-4 (Gan and Südhof, 2019).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Gan and Südhof, 2019
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- Authors
- Gan, K. J., & Südhof, T. C.
- Affiliations
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2019-06-03
- Volume
- 116
- Issue
- 25
- Pages
- 12524-12533
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6589664
- OpenAlex
- W2948768968
- Cited by
- 114
- References
- 61
- Citations by year
- 2026: 7 · 2025: 14 · 2024: 15 · 2023: 15 · 2022: 24 · 2021: 18 · 2020: 17 · 2019: 4
- FWCI
- 7.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Mental Health (MH052804)
- NIMH (MH092931)
- Canadian HIV Trials Network, Canadian Institutes of Health Research (MFE-141209)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- thrombospondin-4, NMDA receptor, synaptogenesis, dendritic branching, synaptic connectivity, serum proteins, aging, synaptic transmission
- MeSH terms
- Age Factors, Aging, Animals, Calcium-Binding Proteins, Cells, Cultured, Female, Humans, Male, Synaptic Transmission, Synapses, Receptors, N-Methyl-D-Aspartate, Extracellular Matrix Proteins, Thrombospondins, Mice
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