Amyloid β Induces the Morphological Neurodegenerative Triad of Spine Loss, Dendritic Simplification, and Neuritic Dystrophies through Calcineurin Activation
Open accessAbstract
Amyloid β (Aβ)-containing plaques are surrounded by dystrophic neurites in the Alzheimer's disease (AD) brain, but whether and how plaques induce these neuritic abnormalities remain unknown. We tested the hypothesis that soluble oligomeric assemblies of Aβ, which surround plaques, induce calcium-mediated secondary cascades that lead to dystrophic changes in local neurites. We show that soluble Aβ oligomers lead to activation of the calcium-dependent phosphatase calcineurin (CaN) (PP2B), which in turn activates the transcriptional factor nuclear factor of activated T cells (NFAT). Activation of these signaling pathways, even in the absence of Aβ, is sufficient to produce a virtual phenocopy of Aβ-induced dystrophic neurites, dendritic simplification, and dendritic spine loss in both neurons in culture and in the adult mouse brain. Importantly, the morphological deficits in the vicinity of Aβ deposits in a mouse model of AD are ameliorated by CaN inhibition, supporting the hypothesis that CaN–NFAT are aberrantly activated by Aβ and that CaN–NFAT activation is responsible for disruption of neuronal structure near plaques. In accord with this, we also detect increased levels of an active form of CaN and NFATc4 in the nuclear fraction from the cortex of patients with AD. Thus, Aβ appears to mediate the neurodegeneration of AD, at least in part, by activation of CaN and subsequent NFAT-mediated downstream cascades.
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No difference was found in the levels of P300, cREL or NFATc in rTg4510 mice.
“No difference was found in the levels of P300, cREL or NFATc (data not shown), transcription factors that have been implicated in different neurodegeneration models (73 -76).”
Aβ oligomer-induced spine loss and dendritic dystrophies can be prevented by calcineurin inhibition.
“Notably, Aβ oligomer–induced spine loss and dendritic dystrophies can be prevented by calcineurin inhibition76.”
From Dendritic spine pathology in neuropsychiatric disorders (2011) · cites this paper as [76]
The toxicity of oligomeric forms of tau and Aβ peptides could be connected with biochemical changes that also produce NPs and NFTs; thus, the oligomeric species may be directly related to the neuropathology, although they are not exactly correlated.
“The toxicity of oligomeric forms of tau and Aβ peptides could be connected with biochemical changes that also produce NPs and NFTs; thus, the oligomeric species may be directly related to the neuropathology, although they are not exactly correlated (90-95).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [93]
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- Authors
- Wu, H.-Y., Hudry, E., Hashimoto, T., Kuchibhotla, K., Rozkalne, A., Fan, Z., Spires-Jones, T., Xie, H., Arbel-Ornath, M., Grosskreutz, C. L., Bacskai, B. J., & Hyman, B. T.
- Affiliations
- Massachusetts General Hospital (US)
- Harvard University (US)
- Massachusetts Eye and Ear Infirmary (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-02-17
- Volume
- 30
- Issue
- 7
- Pages
- 2636-2649
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2841957
- OpenAlex
- W2153438315
- Cited by
- 367
- References
- 63
- Citations by year
- 2026: 11 · 2025: 10 · 2024: 15 · 2023: 19 · 2022: 20 · 2021: 26 · 2020: 25 · 2019: 17 · 2018: 15 · 2017: 22 · 2016: 25 · 2015: 28 · 2014: 25 · 2013: 34 · 2012: 24
- FWCI
- 23.62
- 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)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Cincinnati Children's Hospital Medical Center
- National Institutes of Health (AG08487)
- National Institute on Aging (AG-08487, R01AG008487, P50AG005134, P30AG062421)
- National Eye Institute (R01EY013399, EY13399)
- National Institute of Biomedical Imaging and Bioengineering (EB 000768, R01EB000768)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amyloid-beta, Alzheimer's disease, calcineurin, NFAT, dendritic spine loss, neuritic dystrophy, calcium signaling, neurodegeneration, amyloid plaques, NFATc4
- MeSH terms
- Animals, Calcium, Cells, Cultured, Cerebral Cortex, Embryo, Mammalian, Enzyme-Linked Immunosorbent Assay, Humans, Mice, Transgenic, Microtubule-Associated Proteins, Mutation, Nerve Degeneration, Neurons, Oligopeptides, Peptide Fragments, Postmortem Changes, Subcellular Fractions, Amyloid beta-Peptides, Neurites, Amyloid beta-Protein Precursor, Culture Media, Conditioned, Calcineurin, Protein Transport, Dendritic Spines, Green Fluorescent Proteins, NFATC Transcription Factors, Mice
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