Caspase activation precedes and leads to tangles
Open accessAbstract
Studies of post-mortem tissue have shown that the location of fibrillar tau deposits, called neurofibrillary tangles (NFT), matches closely with regions of massive neuronal death, severe cytological abnormalities, and markers of caspase activation and apoptosis, leading to the idea that tangles cause neurodegeneration in Alzheimer's disease and tau-related frontotemporal dementia. However, using in vivo multiphoton imaging to observe tangles and activation of executioner caspases in living tau transgenic mice (Tg4510 strain), we find the opposite: caspase activation occurs first, and precedes tangle formation by hours to days. New tangles form within a day. After a new tangle forms, the neuron remains alive and caspase activity seems to be suppressed. Similarly, introduction of wild-type 4-repeat tau (tau-4R) into wild-type animals triggered caspase activation, tau truncation and tau aggregation. Adeno-associated virus-mediated expression of a construct mimicking caspase-cleaved tau into wild-type mice led to the appearance of intracellular aggregates, tangle-related conformational- and phospho-epitopes, and the recruitment of full-length endogenous tau to the aggregates. On the basis of these data, we propose a new model in which caspase activation cleaves tau to initiate tangle formation, then truncated tau recruits normal tau to misfold and form tangles. Because tangle-bearing neurons are long-lived, we suggest that tangles are 'off pathway' to acute neuronal death. Soluble tau species, rather than fibrillar tau, may be the critical toxic moiety underlying neurodegeneration.
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Executioner caspases 3 and 7 may contribute to tau pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment.
“Recent evidence suggests that executioner caspases 3 and 7 may contribute to tau, the protein responsible for forming NFTs, pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment (Rissman et al., 2004; Rohn et al., 2008; de Calignon et al., 2010).”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as de Calignon et al., 2010
The supplied Abstract passage says caspases cleave tau at Asp421, producing truncated tau associated with tangles, and reports that a caspase-3/7 probe colocalized with tangles. It implicates caspase 3 and caspase 6 in cleavage, however; it does not establish that caspase 7 cleaves tau or that the resulting fragment is cytotoxic. The paper instead suggests that soluble tau species may be the critical toxic form. (LLM, conf=0.86)
Experimental — accuracy not yet measuredEarly cleavage of tau by caspases may contribute to cognitive decline.
“may contribute to cognitive decline”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as de Calignon et al., 2010
The paper’s main text (labelled Abstract in our copy; page unavailable) proposes that caspase cleavage of tau initiates tangle formation, and its concluding passage suggests that soluble tau species may underlie neurodegeneration. It does not establish or specifically propose that early caspase cleavage contributes to cognitive decline; the memory-related material found is in the References. (LLM, conf=0.83)
Experimental — accuracy not yet measuredEarly cleavage of tau by caspases initiates tau aggregation and phosphorylation.
“the early cleavage of tau by these caspases initiates tau aggregation and phosphorylation”
From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as de Calignon et al., 2010
Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways have been implicated as consequences of tau mislocalization or oligomerization.
“Mitochondrial abnormalities, synaptic loss and dysfunction, altered axonal transport, and activation of cell death pathways (including caspase activation and inflammatory responses) have all been directly or indirectly implicated as consequences of tau mislocalization or oligomerization (20, 40, 43–52).”
From All the Tau We Cannot See (2023) · cites this paper as [43]
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 [43]
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 [43]
Prior data suggest that intracellular tau aggregates can seed aggregation of native tau proteins and propagate their misfolded state in a prion-like manner.
“Recent data suggest that intracellular protein aggregates of tau have the capacity to seed aggregation of native tau proteins and might propagate their misfolded state in a prion-like manner.”
From Propagation of Tau Pathology in a Model of Early Alzheimer's Disease (2012) · cites this paper as de Calignon et al., 2010
The current clinical trial literature is compatible with the idea that AβP-related substances kindle a self-propagating process related to neocortical NFTs.
“The current clinical trial literature is compatible with the idea that AβP-related substances kindle a self-propagating process related to neocortical NFTs, as has been hypothesized (266-269).”
From Correlation of Alzheimer Disease Neuropathologic Changes With Cognitive Status: A Review of the Literature (2012) · cites this paper as [266]
Tau tangles alone are not sufficient to cause neuronal death.
“whereas tau tangles alone are not sufficient to cause neuronal death”
From Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models (2019) · cites this paper as de Calignon et al., 2010
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- Authors
- de Calignon, A., Fox, L. M., Pitstick, R., Carlson, G. A., Bacskai, B. J., Spires-Jones, T. L., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- McLaughlin Research Institute (US)
- Corresponding author
- Hyman, Bradley T.
- Venue
- Nature
- Published
- 2010-03-31
- Volume
- 464
- Issue
- 7292
- Pages
- 1201-1204
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3091360
- OpenAlex
- W2100026237
- Cited by
- 517
- References
- 31
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 12 · 2023: 30 · 2022: 24 · 2021: 28 · 2020: 26 · 2019: 19 · 2018: 26 · 2017: 38 · 2016: 40 · 2015: 39 · 2014: 26 · 2013: 48 · 2012: 54
- FWCI
- 39.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- National Institute on Aging (AG-08487, R01AG026249, R01AG008487, AG026249, P50AG005134, K99AG033670, P30AG062421)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- caspase activation, neurofibrillary tangles, tau protein, Alzheimer's disease, frontotemporal dementia, tau transgenic mice, neuronal survival, neurodegeneration, tau truncation, APOE ε4, APOE3, APOE2, APOE genotype, multiphoton imaging, tau aggregation
- MeSH terms
- Animals, Brain, Enzyme Activation, Humans, Mice, Transgenic, Neurons, Protein Processing, Post-Translational, Solubility, Time Factors, Neurofibrillary Tangles, tau Proteins, Cell Death, Caspases, Mice
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