The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
APP Processing and Synaptic Function
Open accessAbstract
A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
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In the citing paper
“Furthermore, the toxic Ab also decreases synaptic NMDARs, a change that contributes to the impaired LTP (Kamenetz et al. 2003).”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Kamenetz et al. 2003
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 [6]
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 [6]
In the citing paper
“APP is likely important for synapse formation in the developing brain [1], while excess Aβ causes impaired synaptic function [2].”
From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [2]
In the citing paper
“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 [28]
In the citing paper
“Soluble oligomers isolated from AD brain have been shown to potently inhibit long-term potentiation (LTP), enhance long-term depression (LTD) and reduce dendritic spine density in rodent hippocampal slice cultures”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Kamenetz et al., 2003
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 [180]
In the citing paper
“Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.377,378”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [377]
In the citing paper
“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 [85]
In the citing paper
“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 [85]
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 [85]
Citations
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Isolation and quantification of soluble Alzheimer's β-peptide from biological fluids
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Self-citation
Cited by
Sorted by citations
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
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126
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
Pathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052
Metadata
- Authors
- Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., & Malinow, R.
- Affiliations
- State University of New York (US)
- The University of Tokyo (JP)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Johns Hopkins University (US)
- University of Chicago (US)
- Corresponding author
- Malinow, Roberto
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2003-03
- Volume
- 37
- Issue
- 6
- Pages
- 925-937
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1964049915
- Cited by
- 1,644
- References
- 67
- Citations by year
- 2026: 34 · 2025: 49 · 2024: 59 · 2023: 46 · 2022: 57 · 2021: 78 · 2020: 93 · 2019: 81 · 2018: 68 · 2017: 61 · 2016: 103 · 2015: 74 · 2014: 102 · 2013: 71 · 2012: 92
- FWCI
- 35.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (T32GM008444)
- 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 precursor protein, amyloid-beta, Alzheimer's disease, synaptic depression, excitatory synaptic transmission, NMDA receptor, neuronal activity, hippocampal neurons, neuronal hyperactivity, cognitive decline
- MeSH terms
- Alzheimer Disease, Animals, Hippocampus, Humans, Mice, Transgenic, Synaptic Transmission, Neurons, Synapses, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Feedback, Physiological, Mice, Rats
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