The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: implications of prion-like properties
Abstract
The truncated tau protein is a component of the neurofibrillary tangles found in the brains with tauopathies. However, the molecular mechanisms by which the truncated tau fragment causes neurodegeneration remain unknown. Tau pathology was recently suggested to spread through intercellular propagation, and required the formation of 'prion-like' species. We herein identified a new fragment of the tau protein that consisted of four binding domains and a C-terminal tail (Tau-CTF24), but lacked the N-terminal projection domain, and found that it increased with aging in tauopathy model mice (Tg601). Tau-CTF24-like fragments were also present in human brains with tauopathies. A mass spectroscopic analysis revealed that Tau-CTF24 was cleaved behind R242. The digestion of full-length tau (Tau-FL) by calpain produced Tau-CTF24 in vitro and calpain activity increased in old Tg601. Recombinant Tau-CTF24 accelerated heparin-induced aggregation and lost the ability to promote microtubule assembly. When insoluble tau from diseased brains or aggregated recombinant tau was introduced as seeds into SH-SY5Y cells, a larger amount of insoluble tau was formed in cells overexpressing Tau-CTF24 than in those overexpressing Tau-FL. Furthermore, lysates containing the Tau-CTF24 inclusion propagated to naive tau-expressing cells more efficiently than those containing the Tau-FL inclusion. Immunoblot and confocal microscopic analyses revealed that aggregated Tau-CTF24 bound to cells more rapidly and abundantly than aggregated Tau-FL. Our results suggest that Tau-CTF24 contributes to neurodegeneration by enhancing prion-like propagation as well as deteriorating the mechanisms involved in microtubule function.
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Elevated tau243-441 levels are observed in the tau transgenic Tg601 mouse model.
“while elevated tau243–441 levels are observed in the tau transgenic Tg601 mouse model [207, 208].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [207]
Increased calpain activity and levels of tau45-230 have been identified in brain samples from AD and several other tauopathies.
“Increased calpain activity and levels of tau45–230 has been identified in brain samples from AD and several other tauopathies”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [207]
Calpain-mediated tau cleavage generates several truncated tau isoforms, including 17 kDa tau45-230, and 24 kDa tau243-441 products.
“Calpain-mediated tau cleavage generates several truncated tau isoforms, including 17 kDa tau45–230, and 24 kDa tau243–441 products [204, 207].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [207]
Tau243-441 may be pathogenic as it is able to promote tau aggregation and propagation.
“this isoform may be pathogenic as it is able to promote tau aggregation and propagation [207].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [207]
Tau243-441 has no apparent effects on microtubule assembly.
“While tau243–441 has no apparent effects on microtubule assembly”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [207]
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High-fat diet-induced activation of SGK1 promotes Alzheimer’s disease-associated tau pathology
Elahi, M., Motoi, Y., Shimonaka, S., Ishida, Y., Hioki, H., Takanashi, M., Ishiguro, K., Imai, Y., & Hattori, N. (2021) · Human Molecular Genetics · doi:10.1093/hmg/ddab115 · Cited by 57 · see citing works
Self-citationCalpain-mediated tau fragmentation is altered in Alzheimer’s disease progression
Chen, H.-H., Liu, P., Auger, P., Lee, S.-H., Adolfsson, O., Rey-Bellet, L., Lafrance-Vanasse, J., Friedman, B. A., Pihlgren, M., Muhs, A., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-35130-y · Cited by 51 · see citing works
- Authors
- Matsumoto, S.-E., Motoi, Y., Ishiguro, K., Tabira, T., Kametani, F., Hasegawa, M., & Hattori, N.
- Affiliations
- Juntendo University (JP)
- Tokyo Metropolitan Institute of Medical Science (JP)
- Corresponding author
- Motoi, Yumiko
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2015-09-15
- Volume
- 24
- Issue
- 22
- Pages
- 6403-6416
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2177880850
- Cited by
- 66
- References
- 77
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 8 · 2018: 7 · 2017: 5 · 2016: 6
- FWCI
- 4.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) (26460921)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- tau protein, C-terminal fragment, tauopathy, aging, prion-like propagation, neurofibrillary tangles, calpain cleavage, tau aggregation, microtubule assembly, neurodegeneration
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Brain, Calpain, Cells, Cultured, Disease Models, Animal, Humans, Mice, Inbred C57BL, Mice, Transgenic, Microtubules, Phosphorylation, Prions, Neurofibrillary Tangles, tau Proteins, Protein Structure, Tertiary, Tauopathies, Mice
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