Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease
Open accessAbstract
Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.
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A relationship between Aβ production and epileptiform activity was established in the APP/PS1 transgenic mouse model as early as 4 months of age, prior to Aβ plaque deposits forming in the brain parenchyma.
“a relationship between Aβ production and epileptiform activity was established in the APP/PS1 transgenic mouse model as early as 4 months of age, prior to Aβ plaque deposits forming in the brain parenchyma [9, 10].”
From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [9]
The section ‘Overproduction of Aβ is not sufficient to generate EEG abnormalities in double knock-in APP/PS1 mice’ reports no EEG abnormalities in APP/PS1 mice despite elevated Aβ production; these mice were tested at 23–24 months, not 4 months. The paper reports early epileptiform activity in a different model, APP/TTA, by 3 months, and its Discussion argues that Aβ is not the primary cause of those discharges. Page numbers are not available in our copy. (LLM, conf=0.88)
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- Authors
- Born, H. A., Kim, J.-Y., Savjani, R. R., Das, P., Dabaghian, Y. A., Guo, Q., Yoo, J. W., Schuler, D. R., Cirrito, J. R., Zheng, H., Golde, T. E., Noebels, J. L., & Jankowsky, J. L.
- Affiliations
- Texas A&M Health Science Center (US)
- Mayo Clinic (US)
- Rice University (US)
- Baylor College of Medicine (US)
- Washington University in St. Louis (US)
- University of Florida (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-03-12
- Volume
- 34
- Issue
- 11
- Pages
- 3826-3840
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3951689
- OpenAlex
- W2162948131
- Cited by
- 178
- References
- 8
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 15 · 2023: 11 · 2022: 9 · 2021: 19 · 2020: 22 · 2019: 17 · 2018: 14 · 2017: 16 · 2016: 13 · 2015: 14 · 2014: 15
- FWCI
- 12.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- Rice Research Repository (Rice University) (submittedVersion)
- Funders
- National Institutes of Health (DP2OD001734)
- National Institute on Aging (T32AG000183)
- 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 › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- Alzheimer's disease, amyloid precursor protein, amyloid-beta, epileptiform activity, EEG abnormalities, cortical synchronization, APP overexpression, excitation-inhibition balance, gamma-secretase inhibition, amyloid plaques
- MeSH terms
- Alzheimer Disease, Animals, Cerebral Cortex, Disease Models, Animal, Electroencephalography, Female, Humans, Male, Mice, Inbred C57BL, Mice, Transgenic, Models, Neurological, Neural Inhibition, Seizures, Suppression, Genetic, Amyloid beta-Protein Precursor, Transgenes, Entropy, Mice, Presenilin-1, Amyloid Precursor Protein Secretases, Gene Knock-In Techniques
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