title: 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.
authors.affiliation: Department of Diagnosis, Prevention and Treatment of Dementia, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 116-0013, Japan and.
authors.forename: Shin-Ei
authors.initials: SE
authors.lastname: Matsumoto
authors.affiliation: Department of Diagnosis, Prevention and Treatment of Dementia, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 116-0013, Japan and motoi@juntendo.ac.jp.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Motoi
authors.affiliation: Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 116-0013, Japan and.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ishiguro
authors.affiliation: Department of Diagnosis, Prevention and Treatment of Dementia.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tabira
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Kametani
authors.affiliation: Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 156-8506, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Diagnosis, Prevention and Treatment of Dementia, Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 116-0013, Japan and.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Hattori
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008870:Microtubules / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D011328:Prions; D016875:tau Proteins; D002154:Calpain