Dataset Information

Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.

ABSTRACT: Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the cerebrum, in the brainstem, and to a lesser extent in the spinal cord. These features were accompanied by gliosis, neuronal loss, and cerebral atrophy. Accumulated tau was hyperphosphorylated, conformationally changed, ubiquitinated, and sarkosyl-insoluble, with electron microscopy demonstrating wavy filaments. Aged TgTauP301L mice exhibited impairment in hippocampally dependent and independent behavioral paradigms, with impairments closely related to the presence of tau pathologies and levels of insoluble tau protein. We conclude that TgTauP301L mice recreate the substantial phenotypic variation and spectrum of pathologies seen in FTDP-17 patients. Identification of genetic and/or environmental factors modifying the tau phenotype in these mice may shed light on factors modulating human tauopathies. These transgenic mice may aid therapeutic development for FTDP-17 and other diseases featuring accumulations of four-repeat tau, such as Alzheimer's disease, corticobasal degeneration, and progressive supranuclear palsy.

SUBMITTER: Murakami T

PROVIDER: S-EPMC1698843 | biostudies-other | 2006 Oct

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.

Murakami Tetsuro T Paitel Erwan E Kawarabayashi Takeshi T Ikeda Masaki M Chishti M Azhar MA Janus Christopher C Matsubara Etsuro E Sasaki Atsushi A Kawarai Toshitaka T Phinney Amie L AL Harigaya Yasuo Y Horne Patrick P Egashira Nobuaki N Mishima Kenichi K Hanna Amanda A Yang Jing J Iwasaki Katsunori K Takahashi Mitsuo M Fujiwara Michihiro M Ishiguro Koichi K Bergeron Catherine C Carlson George A GA Abe Koji K Westaway David D St George-Hyslop Peter P Shoji Mikio M

The American journal of pathology 20061001 4

Recapitulation of tau pathologies in an animal model has been a long-standing goal in neurodegenerative disease research. We generated transgenic (TgTauP301L) mice expressing a frontotemporal dementia with parkinsonism linked to chromosome 17 (FTPD-17) mutation within the longest form of tau (2N, 4R). TgTauP301L mice developed florid pathology including neuronal pretangles, numerous Gallyas-Braak-positive neurofibrillary tangles, and glial fibrillary tangles in the frontotemporal areas of the ce ...[more]

PMID: 17003492

Similar Datasets

Project description:Frontotemporal lobar degeneration with tau (FTLD-tau) is a group of tauopathies that underlie ∼50% of FTLD cases. Identification of genetic risk variants related to innate/adaptive immunity have highlighted a role for neuroinflammation and neuroimmune interactions in FTLD. Studies have shown microglial and astrocyte activation together with T cell infiltration in the brain of THY-Tau22 tauopathy mice. However, this remains to be confirmed in FTLD-tau patients. We conducted a detailed post-mortem study of FTLD-tau cases including 45 progressive supranuclear palsy with clinical frontotemporal dementia, 33 Pick's disease, 12 FTLD-MAPT and 52 control brains to characterize the link between phosphorylated tau (pTau) epitopes and the innate and adaptive immunity. Tau pathology was assessed in the cerebral cortex using antibodies directed against: Tau-2 (phosphorylated and unphosphorylated tau), AT8 (pSer202/pThr205), AT100 (pThr212/pSer214), CP13 (pSer202), PHF1 (pSer396/pSer404), pThr181 and pSer356. The immunophenotypes of microglia and astrocytes were assessed with phenotypic markers (Iba1, CD68, HLA-DR, CD64, CD32a, CD16 for microglia and GFAP, EAAT2, glutamine synthetase and ALDH1L1 for astrocytes). The adaptive immune response was explored via CD4+ and CD8+ T cell quantification and the neuroinflammatory environment was investigated via the expression of 30 inflammatory-related proteins using V-Plex Meso Scale Discovery. As expected, all pTau markers were increased in FTLD-tau cases compared to controls. pSer356 expression was greatest in FTLD-MAPT cases versus controls (P < 0.0001), whereas the expression of other markers was highest in Pick's disease. Progressive supranuclear palsy with frontotemporal dementia consistently had a lower pTau protein load compared to Pick's disease across tau epitopes. The only microglial marker increased in FTLD-tau was CD16 (P = 0.0292) and specifically in FTLD-MAPT cases (P = 0.0150). However, several associations were detected between pTau epitopes and microglia, supporting an interplay between them. GFAP expression was increased in FTLD-tau (P = 0.0345) with the highest expression in Pick's disease (P = 0.0019), while ALDH1L1 was unchanged. Markers of astrocyte glutamate cycling function were reduced in FTLD-tau (P = 0.0075; Pick's disease: P < 0.0400) implying astrocyte reactivity associated with a decreased glutamate cycling activity, which was further associated with pTau expression. Of the inflammatory proteins assessed in the brain, five chemokines were upregulated in Pick's disease cases (P < 0.0400), consistent with the recruitment of CD4+ (P = 0.0109) and CD8+ (P = 0.0014) T cells. Of note, the CD8+ T cell infiltration was associated with pTau epitopes and microglial and astrocytic markers. Our results highlight that FTLD-tau is associated with astrocyte reactivity, remarkably little activation of microglia, but involvement of adaptive immunity in the form of chemokine-driven recruitment of T lymphocytes.

Project description:The interplay between genes harboring single nucleotide polymorphisms (SNPs) is vital to better understand underlying contributions to the etiology of breast cancer. Much attention has been paid to epistasis between nuclear genes or mutations in the mitochondrial genome. However, there is limited understanding about the epistatic effects of genetic variants in the nuclear and mitochondrial genomes jointly on breast cancer. We tested the interaction of germline SNPs in the mitochondrial (mtSNPs) and nuclear (nuSNPs) genomes of female breast cancer patients in The Cancer Genome Atlas (TCGA) for association with morphological features extracted from hematoxylin and eosin (H&E)-stained pathology images. We identified 115 significant (q-value < 0.05) mito-nuclear interactions that increased nuclei size by as much as 12%. One interaction between nuSNP rs17320521 in an intron of the WSC Domain Containing 2 (WSCD2) gene and mtSNP rs869096886, a synonymous variant mapped to the mitochondrially-encoded NADH dehydrogenase 4 (MT-ND4) gene, was confirmed in an independent breast cancer data set from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). None of the 10 mito-nuclear interactions identified from non-diseased female breast tissues from the Genotype-Expression (GTEx) project resulted in an increase in nuclei size. Comparisons of gene expression data from the TCGA breast cancer patients with the genotype homozygous for the minor alleles of the SNPs in WSCD2 and MT-ND4 versus the other genotypes revealed core transcriptional regulator interactions and an association with insulin. Finally, a Cox proportional hazards ratio = 1.7 (C.I. 0.98-2.9, p-value = 0.042) and Kaplan-Meier plot suggest that the TCGA female breast cancer patients with low gene expression of WSCD2 coupled with large nuclei have an increased risk of mortality. The intergenomic dependency between the two variants may constitute an inherent susceptibility of a more severe form of breast cancer and points to genetic targets for further investigation of additional determinants of the disease.

Dataset Information

Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.

Publications

Cortical neuronal and glial pathology in TgTauP301L transgenic mice: neuronal degeneration, memory disturbance, and phenotypic variation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets