Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid-β In Vivo
Open accessAbstract
Aggregation of amyloid-beta (Abeta) peptide into soluble and insoluble forms within the brain extracellular space is central to the pathogenesis of Alzheimer's disease. Full-length amyloid precursor protein (APP) is endocytosed from the cell surface into endosomes where it is cleaved to produce Abeta. Abeta is subsequently released into the brain interstitial fluid (ISF). We hypothesized that synaptic transmission results in more APP endocytosis, thereby increasing Abeta generation and release into the ISF. We found that inhibition of clathrin-mediated endocytosis immediately lowers ISF Abeta levels in vivo. Two distinct methods that increased synaptic transmission resulted in an elevation of ISF Abeta levels. Inhibition of endocytosis, however, prevented the activity-dependent increase in Abeta. We estimate that approximately 70% of ISF Abeta arises from endocytosis-associated mechanisms, with the vast majority of this pool also dependent on synaptic activity. These findings have implications for AD pathogenesis and may provide insights into therapeutic intervention.
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Synaptic activity is one key regulator of brain Aβ production.
“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 [4]
Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracellular fluid or interstitial fluid (ISF).
“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 [4]
Synaptic activity regulates Aβ levels through a presynaptic mechanism that is dependent on APP endocytosis and cleavage.
“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 [4]
Effect sizes of significant loci obtained from genome-wide studies are over-estimates of the true effects.
“However, it is widely acknowledged that effect sizes of significant loci obtained from genomewide studies are over-estimates of the true effects 46 .”
From Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease (2009) · cites this paper as [46]
One explanation for Aβ aggregation within the DMN is that deposition of Aβ fibrils could be caused by high neuronal activity within the DMN, supported by animal studies showing Aβ secretion and deposition is enhanced by neuronal activity.
“One explanation is that the deposition of Aβ fibrils could be caused by the high neuronal activity within the DMN, which is supported by animal studies showing that Aβ secretion and deposition is enhanced by neuronal activity27–29.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [27]
APP is transported down both axons and dendrites.
“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [25]
Aβ appears to be generated preferentially at synapses.
“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [25]
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- Authors
- Cirrito, J. R., Kang, J.-E., Lee, J., Stewart, F. R., Verges, D. K., Silverio, L. M., Bu, G., Mennerick, S., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Cirrito, John R.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-04
- Volume
- 58
- Issue
- 1
- Pages
- 42-51
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC2390913
- OpenAlex
- W2060351135
- Cited by
- 635
- References
- 51
- Citations by year
- 2026: 12 · 2025: 24 · 2024: 26 · 2023: 34 · 2022: 23 · 2021: 46 · 2020: 29 · 2019: 37 · 2018: 33 · 2017: 42 · 2016: 29 · 2015: 34 · 2014: 44 · 2013: 47 · 2012: 49
- FWCI
- 27.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- Funders
- Israel Science Foundation
- National Institute on Aging (R01AG027924, R01AG013956, R37AG027924, AG027924, K01AG029524, R37AG013956, AG13956, AG029524)
- National Institute of Mental Health (MH-78823, R01MH078823)
- National Institute on Drug Abuse (DA07261, T32DA007261)
- National Institute of Neurological Disorders and Stroke (NS-54174, R01NS054174, P30NS057105)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta, endocytosis, clathrin-mediated endocytosis, amyloid precursor protein, synaptic transmission, brain interstitial fluid, Alzheimer's disease, endosomes, activity-dependent release, APP processing
- MeSH terms
- Alzheimer Disease, Animals, Endocytosis, Mice, Inbred C57BL, Mice, Transgenic, Synaptic Transmission, Synapses, Amyloid beta-Peptides, Mice
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