Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) is characterized by a progressive dysfunction of central neurons. Recent experimental evidence indicates that in the cortex, in addition to the silencing of a fraction of neurons, other neurons are hyperactive in amyloid-β (Aβ) plaque-enriched regions. However, it has remained unknown what comes first, neuronal silencing or hyperactivity, and what mechanisms might underlie the primary neuronal dysfunction. Here we examine the activity patterns of hippocampal CA1 neurons in a mouse model of AD in vivo using two-photon Ca(2+) imaging. We found that neuronal activity in the plaque-bearing CA1 region of older mice is profoundly altered. There was a marked increase in the fractions of both silent and hyperactive neurons, as previously also found in the cortex. Remarkably, in the hippocampus of young mice, we observed a selective increase in hyperactive neurons already before the formation of plaques, suggesting that soluble species of Aβ may underlie this impairment. Indeed, we found that acute treatment with the γ-secretase inhibitor LY-411575 reduces soluble Aβ levels and rescues the neuronal dysfunction. Furthermore, we demonstrate that direct application of soluble Aβ can induce neuronal hyperactivity in wild-type mice. Thus, our study identifies hippocampal hyperactivity as a very early functional impairment in AD transgenic mice and provides direct evidence that soluble Aβ is crucial for hippocampal hyperactivity.
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The early abnormal neuronal hyperactivity phenotype in AppNL-G-F mice has been shown to be dependent on soluble amyloid beta.
“which has been shown to be dependent on soluble Aβ [38–40]”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [39]
The Discussion reports that soluble Aβ causally promotes early hippocampal hyperactivity: reducing soluble Aβ reversed hyperactivity, while applying it induced hyperactivity in wild-type mice. But the Results identify the study mice as APPswe/PS1 G384A transgenic mice, not AppNL-G-F mice, so this source does not establish the phenotype’s dependence on soluble Aβ in the specified model. Page numbers are not available in the supplied copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredEffects of amyloid beta on neuronal activity and synaptic function often stem from soluble aggregates similar to those produced in much greater numbers by oligodendrocytes.
“Rather than being plaque dependent, the effects of Aβ on neuronal activity and synaptic function often stem from soluble aggregates similar to those we see produced in much greater numbers by oligodendrocytes [32,39].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [39]
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The Effects of Amyloid and Tau on Functional Network Connectivity in Older Populations
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Lomoio, S., Pandey, R. S., Rouleau, N., Menicacci, B., Kim, W., Cantley, W. L., Haydon, P. G., Bennett, D. A., Young-Pearse, T. L., Carter, G. W., et al. (2023) · Molecular Psychiatry · doi:10.1038/s41380-023-02147-3 · Cited by 25 · see citing works
Chen, L., Christenson Wick, Z., Vetere, L. M., Vaughan, N., Jurkowski, A., Galas, A., Diego, K. S., Philipsberg, P. A., Soler, I., Feng, Y., et al. (2023) · The Journal of Neuroscience · doi:10.1523/jneurosci.1204-23.2023 · Cited by 21 · see citing works
- Authors
- Busche, M. A., Chen, X., Henning, H. A., Reichwald, J., Staufenbiel, M., Sakmann, B., & Konnerth, A.
- Affiliations
- Center for Integrated Protein Science Munich (DE)
- Novartis Institutes for BioMedical Research (CH)
- Technical University of Munich (DE)
- Corresponding author
- Konnerth, Arthur
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2012-05-16
- Volume
- 109
- Issue
- 22
- Pages
- 8740-8745
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3365221
- OpenAlex
- W2035466313
- Cited by
- 715
- References
- 48
- Citations by year
- 2026: 56 · 2025: 72 · 2024: 78 · 2023: 71 · 2022: 66 · 2021: 76 · 2020: 57 · 2019: 41 · 2018: 38 · 2017: 35 · 2016: 38 · 2015: 27 · 2014: 31 · 2013: 20 · 2012: 7
- FWCI
- 18.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Technische Universität München
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, soluble amyloid-beta, CA1 pyramidal neurons, neuronal hyperactivity, neuronal silencing, amyloid plaques, gamma-secretase inhibition, two-photon calcium imaging, transgenic mouse model
- MeSH terms
- Age Factors, Alanine, Alzheimer Disease, Animals, Azepines, Calcium, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Neurons, Amyloid beta-Peptides, Microscopy, Fluorescence, Multiphoton, Mice, Amyloid Precursor Protein Secretases, CA1 Region, Hippocampal, Plaque, Amyloid
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