In Vivo Imaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons
Open accessAbstract
Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.
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In Tg4510 P301L mice, caspase activation and neuronal death often precede tangle formation.
“For example, through direct visualization of the cortex of Tg4510 P301L mice by multiphoton microscopy, Hyman and colleagues were able to determine that caspase activation, and neuronal death, appeared in many instances to precede tangle formation.”
From All the Tau We Cannot See (2023) · cites this paper as [51]
Tangles forming did not lead to neuronal death over several-month imaging period in Tg4510 P301L mice.
“Indeed, tangles forming did not lead to neuronal death over the course of the several-month imaging period (43, 51).”
From All the Tau We Cannot See (2023) · cites this paper as [51]
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Self-citation
- Authors
- Spires-Jones, T. L., de Calignon, A., Matsui, T., Zehr, C., Pitstick, R., Wu, H.-Y., Osetek, J. D., Jones, P. B., Bacskai, B. J., Feany, M. B., Carlson, G. A., Ashe, K. H., Lewis, J., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Mayo Clinic (US)
- McLaughlin Research Institute (US)
- University of Minnesota (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-01-23
- Volume
- 28
- Issue
- 4
- Pages
- 862-867
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6670992
- OpenAlex
- W2092885373
- Cited by
- 137
- References
- 27
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 4 · 2018: 6 · 2017: 4 · 2016: 6 · 2015: 7 · 2014: 7 · 2013: 20 · 2012: 8
- FWCI
- 12.91
- 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, cc-by-nc-sa)
- Funders
- National Institutes of Health (5r01ns046355-03, AG08487)
- National Institute on Aging (AG-08487, R01AG026249, AG00277, R01AG008487, AG26249, R01AG026252, T32AG000277, P50AG005134, P30AG062421)
- National Institute of Neurological Disorders and Stroke (R01-NS046355, R01-NS46355)
- National Institute of Biomedical Imaging and Bioengineering (EB-00768, R01EB000768)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurofibrillary tangles, caspase activation, neuronal cell death, apoptosis, Alzheimer's disease, tauopathy, rTg4510 mice, executioner caspases, neuronal loss
- MeSH terms
- Animals, Enzyme Activation, Humans, Mice, Transgenic, Neurons, Neurofibrillary Tangles, tau Proteins, Cell Death, Apoptosis, Caspases, Microscopy, Fluorescence, Multiphoton, Mice
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