The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
Open accessAbstract
Aggregation of the amyloid-beta (Abeta) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Abeta aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Abeta levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Abeta levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Abeta metabolism and ultimately region-specific Abeta deposition. The findings also have important implications for treatment development.
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In the citing paper
“The lower abundance of plaques in the white matter could further be explained by the evidence that most neuronal Aβ is secreted at presynaptic terminals, thus favouring plaque deposition in the grey matter [50,51].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [51]
In the citing paper
“Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracellular fluid or interstitial fluid (ISF) (4–6).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [5]
In the citing paper
“TTX dramatically reduces neuronal activity and ISF Aβ levels in vivo (5).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [5]
In the citing paper
“Synaptic activity is one key regulator of brain Aβ production.”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [5]
In the citing paper
“Synaptic activity is known to regulate Aβ levels through a presynaptic mechanism that is dependent on APP endocytosis and cleavage (4, 5) and through neurotransmitter-activated second messenger signaling pathways that alter APP processing into Aβ (7, 11, 12, 31).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [5]
In the citing paper
“Proteins linked to neurodegenerative diseases, including β-amyloid (Aβ) (8), α-synuclein (9), and tau (10), are present in the interstitial space surrounding cells of the brain.”
From Sleep Drives Metabolite Clearance from the Adult Brain (2013) · cites this paper as [8]
In the citing paper
“Overall, we feel we can confidently state APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [181]
In the citing paper
“Although the aggregates have been considered to be toxic, soluble Aβ at physiological levels have been identified to have biological functions, including enhancement of long-term potentiation (LTP),355–358 stimulation of neuronal differentiation,359 improvement of the brain’s ability to recover from injuries,360–363 inhibition of oxidative stress,364 antimicrobial activity365 and tumor suppression”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [355]
In the citing paper
“Extracellular occurrence of oligomers is consistent with the rapid outpouring of Aβ, and perhaps small oligomers, into brain interstitial fluid, measured by microdialysis in mouse models and humans (Cirrito et al., 2005; Kang et al., 2007; Kang et al., 2009).”
From The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease (2011) · cites this paper as Cirrito et al., 2005
In the citing paper
“Synaptic activity has been shown to increase the secretion of Aβ in hippocampal slices and living rodent brain [26, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [26]
Citations
Cites
A default mode of brain function
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Powers, W. J., Gusnard, D. A., & Shulman, G. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.676 · Cited by 12,190
Alzheimer's Disease: Genes, Proteins, and Therapy
Selkoe, D. J. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.2.741 · Cited by 6,063
Searching for a baseline: Functional imaging and the resting human brain
Gusnard, D. A., & Raichle, M. E. (2001) · Nature Reviews Neuroscience · doi:10.1038/35094500 · Cited by 3,371
Buckner, R. L., Snyder, A. Z., Shannon, B. J., LaRossa, G., Sachs, R., Fotenos, A. F., Sheline, Y. I., Klunk, W. E., Mathis, C. A., Morris, J. C., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2177-05.2005 · Cited by 2,140
APP Processing and Synaptic Function
Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., & Malinow, R. (2003) · Neuron · doi:10.1016/s0896-6273(03)00124-7 · Cited by 1,644
GSK-3α regulates production of Alzheimer's disease amyloid-β peptides
Phiel, C. J., Wilson, C., Lee, V. M. ‐., & Klein, P. S. (2003) · Nature · doi:10.1038/nature01640 · Cited by 1,211
Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H., & Younkin, S. G. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00372.2001 · Cited by 1,053 · cited 1×
“Data represent mean 6 SEM. in humans, results in early onset, familial AD and develop Ab deposition in amyloid plaques beginning at about 8–9 months of age (Kawarabayashi et al., 2001).”
BackgroundEnvironmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice
Lazarov, O., Robinson, J., Tang, Y.-P., Hairston, I. S., Korade-Mirnics, Z., Lee, V. M.-Y., Hersh, L. B., Sapolsky, R. M., Mirnics, K., & Sisodia, S. S. (2005) · Cell · doi:10.1016/j.cell.2005.01.015 · Cited by 885
Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors
Cartmell, J., & Schoepp, D. D. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0750889.x · Cited by 883
Self-citationEvidence that production and release of amyloid beta-protein involves the endocytic pathway
Koo, E. H., & Squazzo, S. L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32449-3 · Cited by 829
Cited by
Sorted by citations
The Brain's Default Network: Anatomy, Function, and Relevance to Disease
Buckner, R. L., Andrews‐Hanna, J. R., & Schacter, D. L. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1440.011 · Cited by 9,761
Sleep Drives Metabolite Clearance from the Adult Brain
Xie, L., Kang, H., Xu, Q., Chen, M. J., Liao, Y., Thiyagarajan, M., O’Donnell, J., Christensen, D. J., Nicholson, C., Iliff, J. J., et al. (2013) · Science · doi:10.1126/science.1241224 · Cited by 5,411
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
Self-citation
Metadata
- Authors
- Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University of Arizona (US)
- Eli Lilly (United States) (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2005-12
- Volume
- 48
- Issue
- 6
- Pages
- 913-922
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2046952010
- Cited by
- 1,265
- References
- 38
- Citations by year
- 2026: 34 · 2025: 62 · 2024: 76 · 2023: 69 · 2022: 62 · 2021: 83 · 2020: 93 · 2019: 76 · 2018: 58 · 2017: 85 · 2016: 52 · 2015: 62 · 2014: 81 · 2013: 70 · 2012: 69
- FWCI
- 15.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG11355, AG13956, P01AG011355)
- National Institute on Drug Abuse (DA70261)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, synaptic activity, interstitial fluid, Alzheimer's disease, synaptic vesicle exocytosis, amyloid-beta metabolism, microdialysis, field potential recording
- MeSH terms
- Action Potentials, Alzheimer Disease, Animals, Brain, Exocytosis, Female, Hippocampus, Male, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Synaptic Transmission, Organ Culture Techniques, Synaptic Vesicles, Amyloid beta-Peptides, Microdialysis, Presynaptic Terminals, Mice, Knockout, Patch-Clamp Techniques, Perforant Pathway, Extracellular Fluid, Mice, Plaque, Amyloid
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