Amyloid precursor protein (APP) regulates synaptic structure and function
Open accessAbstract
The amyloid precursor protein (APP) plays a critical role in Alzheimer's disease (AD) pathogenesis. APP is proteolytically cleaved by β- and γ-secretases to generate the amyloid β-protein (Aβ), the core protein component of senile plaques in AD. It is also cleaved by α-secretase to release the large soluble APP (sAPP) luminal domain that has been shown to exhibit trophic properties. Increasing evidence points to the development of synaptic deficits and dendritic spine loss prior to deposition of amyloid in transgenic mouse models that overexpress APP and Aβ peptides. The consequence of loss of APP, however, is unsettled. In this study, we investigated whether APP itself plays a role in regulating synaptic structure and function using an APP knock-out (APP-/-) mouse model. We examined dendritic spines in primary cultures of hippocampal neurons and CA1 neurons of hippocampus from APP-/- mice. In the cultured neurons, there was a significant decrease (~35%) in spine density in neurons derived from APP-/- mice compared to littermate control neurons that were partially restored with sAPPα-conditioned medium. In APP-/- mice in vivo, spine numbers were also significantly reduced but by a smaller magnitude (~15%). Furthermore, apical dendritic length and dendritic arborization were markedly diminished in hippocampal neurons. These abnormalities in neuronal morphology were accompanied by reduction in long-term potentiation. Strikingly, all these changes in vivo were only seen in mice that were 12-15 months in age but not in younger animals. We propose that APP, specifically sAPP, is necessary for the maintenance of dendritic integrity in the hippocampus in an age-associated manner. Finally, these age-related changes may contribute to AD pathology independent of Aβ-mediated synaptic toxicity.
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A thirty-five percent decrease in spine density has been observed in neurons derived from APP−/− mice, which was partially rescued by sAPP-α conditioned medium.
“Thirty-five percent decrease in spine density has been observed in neurons derived from APP−/− mice, which was partially rescued by sAPP-α conditioned medium [136].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [136]
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“The different effects on spine number between sAPPα and β are intriguing as this supports the concept that a trophic domain is encoded in the 17 amino acids at the C-terminus of sAPPα that is lacking in sAPPβ (Mattson, 1997).”
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- Authors
- Tyan, S.-H., Shih, A. Y.-J., Walsh, J. J., Maruyama, H., Sarsoza, F., Ku, L., Eggert, S., Hof, P. R., Koo, E. H., & Dickstein, D. L.
- Affiliations
- University of California San Diego (US)
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Tyan, Sheue-Houy
- Dickstein, Dara L.
- Venue
- Molecular and Cellular Neuroscience
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 51
- Issue
- 1-2
- Pages
- 43-52
- ISSN
- 1044-7431 (ISSN-L)
- PMC
- PMC3538857
- OpenAlex
- W2082617364
- Cited by
- 191
- References
- 2
- Citations by year
- 2026: 11 · 2025: 11 · 2024: 10 · 2023: 13 · 2022: 13 · 2021: 20 · 2020: 13 · 2019: 16 · 2018: 11 · 2017: 26 · 2016: 10 · 2015: 8 · 2014: 19 · 2013: 10
- FWCI
- 7.45
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Molecular and Cellular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of California, San Diego
- National Institute on Aging (P50AG005138, R01AG032179)
- National Cancer Institute (P30CA023100)
- Topics
- Health Sciences › Medicine › Physiology › 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, APP knockout mice, dendritic spines, synaptic structure, soluble APP alpha, long-term potentiation, hippocampal neurons, dendritic branching, dendritic length, Alzheimer's disease
- MeSH terms
- Animals, Hippocampus, Mice, Inbred C57BL, Synapses, Amyloid beta-Protein Precursor, Long-Term Potentiation, Mice, Knockout, Dendritic Spines, Mice
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