by Keyword: Htau

Ferrer I, Andrés-Benito P, Carmona M, Del Rio JA, (2022). Common and Specific Marks of Different Tau Strains Following Intra-Hippocampal Injection of AD, PiD, and GGT Inoculum in hTau Transgenic Mice International Journal Of Molecular Sciences 23, 15940

Ferrer, I, Andres-Benito, P, Ausin, K, Cartas-Cejudo, P, Lachen-Montes, M, del Rio, JA, Fernandez-Irigoyen, J, Santamaria, E, (2022). Dysregulated Brain Protein Phosphorylation Linked to Increased Human Tau Expression in the hTau Transgenic Mouse Model International Journal Of Molecular Sciences 23, 6427

Altered protein phosphorylation is a major pathologic modification in tauopathies and Alzheimer's disease (AD) linked to abnormal tau fibrillar deposits in neurofibrillary tangles (NFTs) and pre-tangles and beta-amyloid deposits in AD. hTau transgenic mice, which express 3R and less 4R human tau with no mutations in a murine knock-out background, show increased tau deposition in neurons but not NFTs and pre-tangles at the age of nine months. Label-free (phospho)proteomics and SWATH-MS identified 2065 proteins in hTau and wild-type (WT) mice. Only six proteins showed increased levels in hTau; no proteins were down-regulated. Increased tau phosphorylation in hTau was detected at Ser199, Ser202, Ser214, Ser396, Ser400, Thr403, Ser404, Ser413, Ser416, Ser422, Ser491, and Ser494, in addition to Thr181, Thr231, Ser396/Ser404, but not at Ser202/Thr205. In addition, 4578 phosphopeptides (corresponding to 1622 phosphoproteins) were identified in hTau and WT mice; 64 proteins were differentially phosphorylated in hTau. Sixty proteins were grouped into components of membranes, membrane signaling, synapses, vesicles, cytoskeleton, DNA/RNA/protein metabolism, ubiquitin/proteasome system, cholesterol and lipid metabolism, and cell signaling. These results showed that over-expression of human tau without pre-tangle and NFT formation preferentially triggers an imbalance in the phosphorylation profile of specific proteins involved in the cytoskeletal-membrane-signaling axis.

JTD Keywords: Aggregation, Alzheimers-disease, Animal-models, Cytoskeleton, Htau, Membrane, Mice, Networks, Pathology, Phosphoproteome analysis, Phosphorylation, Synapsis, Tau, Tauopathies, Tauopathy

Andrés-Benito, Pol, Carmona, Margarita, Jordán, Mónica, Fernández-Irigoyen, Joaquín, Santamaría, Enrique, del Rio, José Antoni, Ferrer, Isidro, (2022). Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum International Journal Of Molecular Sciences 23, 718

Several studies have demonstrated the different characteristics of tau seeding and spreading following intracerebral inoculation in murine models of tau-enriched fractions of brain homogenates from AD and other tauopathies. The present study is centered on the importance of host tau in tau seeding and the molecular changes associated with the transformation of host tau into abnormal tau. The brains of three adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWT (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD and control cases. The present study reveals that (a) host tau is mandatory for tau seeding and spreading following tau inoculation from sarkosyl-insoluble fractions obtained from AD brains; (b) tau seeding does not occur following intracerebral inoculation of sarkosyl-insoluble fractions from controls; (c) tau seeding and spreading are characterized by variable genotype-dependent tau phosphorylation and tau nitration, MAP2 phosphorylation, and variable activation of kinases that co-localize with abnormal tau deposits; (d) transformation of host tau into abnormal tau is an active process associated with the activation of specific kinases; (e) tau seeding is accompanied by modifications in tau splicing, resulting in the expression of new 3Rtau and 4Rtau isoforms, thus indicating that inoculated tau seeds have the capacity to model exon 10 splicing of the host mapt or MAPT with a genotype-dependent pattern; (e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits, are dependent on the host tau of mice injected with identical AD tau inocula.

JTD Keywords: 3rtau and 4rtau, alzheimer's disease, alzheimer’s disease, brains, granulovacuolar degeneration, host tau, htau, intranuclear distribution, messenger-rna, pathological tau, propagation, protein-kinases, seeding and spreading, tauopathies, transmission, 3rtau and 4rtau, Alzheimers-disease, Alzheimer’s disease, Host tau, Htau, Seeding and spreading, Tauopathies