title: Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein.
abstract: The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis. According to light microscopy, many nerve cells in brain and spinal cord were strongly immunoreactive for hyperphosphorylated tau. According to electron microscopy, abundant filaments made of hyperphosphorylated tau protein were present. The majority of filaments resembled the half-twisted ribbons described previously in cases of FTDP-17, with a minority of filaments resembling the paired helical filaments of Alzheimer's disease. Sarkosyl-insoluble tau from brains and spinal cords of transgenic mice ran as a hyperphosphorylated 64 kDa band, the same apparent molecular mass as that of the 383 aa tau isoform in the human tauopathies. Perchloric acid-soluble tau was also phosphorylated at many sites, with the notable exception of serine 214. In the spinal cord, neurodegeneration was present, as indicated by a 49% reduction in the number of motor neurons. No evidence for apoptosis was obtained, despite the extensive colocalization of hyperphosphorylated tau protein with activated MAP kinase family members. The latter may be involved in the hyperphosphorylation of tau.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 2QH, United Kingdom.
authors.forename: Bridget
authors.initials: B
authors.lastname: Allen
authors.forename: Esther
authors.initials: E
authors.lastname: Ingram
authors.forename: Masaki
authors.initials: M
authors.lastname: Takao
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Smith
authors.forename: Ross
authors.initials: R
authors.lastname: Jakes
authors.forename: Kanwar
authors.initials: K
authors.lastname: Virdee
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Yoshida
authors.forename: Max
authors.initials: M
authors.lastname: Holzer
authors.forename: Molly
authors.initials: M
authors.lastname: Craxton
authors.forename: Piers C
authors.initials: PC
authors.lastname: Emson
authors.forename: Cristiana
authors.initials: C
authors.lastname: Atzori
authors.forename: Antonio
authors.initials: A
authors.lastname: Migheli
authors.forename: R Anthony
authors.initials: RA
authors.lastname: Crowther
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
authors.forename: Michel
authors.initials: M
authors.lastname: Goedert
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D052160:Benzothiazoles; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001923:Brain Chemistry; D002452:Cell Count; D004195:Disease Models, Animal; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D020335:Paraparesis / Q000209:etiology / Q000503:physiopathology; D010641:Phenotype; D010766:Phosphorylation; D012521:Sarcosine / Q000031:analogs & derivatives* / Q000737:chemistry; D012995:Solubility; D013116:Spinal Cord / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D013844:Thiazoles; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D052160:Benzothiazoles; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T; C025231:sarkosyl; D012521:Sarcosine