scholarly journals Host Tau Genotype Specifically Designs and Regulates Tau Seeding and Spreading and Host Tau Transformation Following Intrahippocampal Injection of Identical Tau AD Inoculum

2022 ◽  
Vol 23 (2) ◽  
pp. 718
Author(s):  
Pol Andrés-Benito ◽  
Margarita Carmona ◽  
Mónica Jordán ◽  
Joaquín Fernández-Irigoyen ◽  
Enrique Santamaría ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Tau Phosphorylation ◽  
Murine Models ◽  
Knock Out ◽  
Intracerebral Inoculation ◽  
Intrahippocampal Injection ◽  
Different Characteristics ◽  
And Control ◽  
Exon 10

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.

scholarly journals Host Tau Genotype Specifically Regulates and Designs Tau Seeding and Spreading Following Intracerebral Injection of Identical Tau ADInoculum

2021 ◽  
Author(s):  
Pol Andrés-Benito ◽  
Margarita Carmona ◽  
Mónica Jordán ◽  
José Antonio del Rio ◽  
Isidro Ferrer
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Host Cells ◽  
Intracerebral Injection ◽  
Molecular Response ◽  
Knock Out ◽  
Ca1 Neurons ◽  
Variable Expression ◽  
Gsk 3Β ◽  
P301s Mutation

Abstract BackgroundSeveral studies have demonstrated the capacity for seeding and spreading of tau-enriched fractions of brain homogenates from AD and other human and mouse tauopathies following intracerebral inoculation into transgenic mice bearing human tau or mutant human tau and into WT mice. However, little attention has been paid about the importance of host tau in tau seeding. MethodsThe brains of four adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), P301S (human 4Rtau expressing the P301S mutation), 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 case. ResultsNo tau deposits were identified in inoculated mtWT mice. Involvement of CA1 neurons was higher and that of oligodendrocytes lower in inoculated hTau when compared with inoculated WT and P301S mice. tau-P Ser422, PHF1, and MAP2-P immunoreactivity was moderate or weak in WT and P301S, but strong i in inoculated hTau mice. p38-P and SAPK/JNK-P were observed in recruited phospho-tau deposits in inoculated WT, P301S, and hTau mice. However, CK1-δ, GSK-3β-P Ser9, AKT-P Ser473, PKAα/β-P Tyr197, and CLK1 were identified in neurons with tau deposits only in inoculated hTau. Finally, 3Rtau deposits predominated in inoculated WT and P301S, and 4Rtau deposits in hTau transgenic mice. ConclusionsOur results reveal that a) host tau is mandatory for tau seeding and spreading following tau inoculation; b) tau seeding and spreading is characterized by major genotype-dependent biochemical changes linked to post-translational tau modifications including tau phosphorylation and tau nitration at different sites, c) it is accompanied by genotype-dependent activation of various kinases thus pointing to a complex molecular response in the receptive host cells; d) tau seeding and spreading is accompanied by modifications in tau splicing with variable expression of new 3Rtau and 4Rtau isoforms; e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits are dependent on the host tau genotypes injected with identical AD tau inoculum.

scholarly journals Host Tau Genotype Specifically Regulates and Designs Tau Seeding and Spreading Following Intracerebral Injection of Identical Tau AD Inoculum

2021 ◽  
Author(s):  
Pol Andrés-Benito ◽  
Margarita Carmona ◽  
Mónica Jordán ◽  
José Antonio del Rio ◽  
Isidro Ferrer
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Host Cells ◽  
Intracerebral Injection ◽  
Molecular Response ◽  
Knock Out ◽  
Ca1 Neurons ◽  
Variable Expression ◽  
Gsk 3Β ◽  
P301s Mutation

Abstract Background: Several studies have demonstrated the capacity for seeding and spreading of tau-enriched fractions of brain homogenates from AD and other human and mouse tauopathies following intracerebral inoculation into transgenic mice bearing human tau or mutant human tau and into WT mice. However, little attention has been paid about the importance of host tau in tau seeding. Methods: The brains of four adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), P301S (human 4Rtau expressing the P301S mutation), 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 case. Results: No tau deposits were identified in inoculated mtWT mice. Involvement of CA1 neurons was higher and that of oligodendrocytes lower in inoculated hTau when compared with inoculated WT and P301S mice. tau-P Ser422, PHF1, and MAP2-P immunoreactivity was moderate or weak in WT and P301S, but strong in inoculated hTau mice. p38-P and SAPK/JNK-P were observed in recruited phospho-tau deposits in inoculated WT, P301S, and hTau mice. However, CK1-δ, GSK-3β-P Ser9, AKT-P Ser473, PKAα/β-P Tyr197, and CLK1 were identified in neurons with tau deposits only in inoculated hTau. Finally, 3Rtau deposits predominated in inoculated WT and P301S, and 4Rtau deposits in hTau transgenic mice. Conclusions: Our results reveal that a) host tau is mandatory for tau seeding and spreading following tau inoculation; b) tau seeding and spreading is characterized by major genotype-dependent biochemical changes linked to post-translational tau modifications including tau phosphorylation and tau nitration at different sites, c) it is accompanied by genotype-dependent activation of various kinases thus pointing to a complex molecular response in the receptive host cells; d) tau seeding and spreading is accompanied by modifications in tau splicing with variable expression of new 3Rtau and 4Rtau isoforms; e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits are dependent on the host tau genotypes injected with identical AD tau inoculum.

scholarly journals Antisense Oligonucleotide-Mediated Reduction of HDAC6 Does Not Reduce Tau Pathology in P301S Tau Transgenic Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonio Valencia ◽  
Veronica L. Reinhart Bieber ◽  
Bekim Bajrami ◽  
Galina Marsh ◽  
Stefan Hamann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Antisense Oligonucleotide ◽  
Tau Phosphorylation ◽  
Histone Deacetylase 6 ◽  
Tau Pathology ◽  
Tau Aggregation ◽  
The Brain ◽  
Mediated Reduction ◽  
Tau Acetylation

Acetylation of tau protein is dysregulated in Alzheimer's Disease (AD). It has been proposed that acetylation of specific sites in the KXGS motif of tau can regulate phosphorylation of nearby residues and reduce the propensity of tau to aggregate. Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme involved in deacetylation of multiple targets, including tau, and it has been suggested that inhibition of HDAC6 would increase tau acetylation at the KXGS motifs and thus may present a viable therapeutic approach to treat AD. To directly test the contribution of HDAC6 to tau pathology, we intracerebroventricularly injected an antisense oligonucleotide (ASO) directed against HDAC6 mRNA into brains of P301S tau mice (PS19 model), which resulted in a 70% knockdown of HDAC6 protein in the brain. Despite a robust decrease in levels of HDAC6, no increase in tau acetylation was observed. Additionally, no change of tau phosphorylation or tau aggregation was detected upon the knockdown of HDAC6. We conclude that HDAC6 does not impact tau pathology in PS19 mice.

Tau phosphorylation in transgenic mice expressing glycogen synthase kinase-3β transgenes

Neuroreport ◽  
1997 ◽  
Vol 8 (15) ◽  
pp. 3251-3255 ◽  
Author(s):  
Janet Brownlees ◽  
Nicholas G. Irving ◽  
Jean-Pierre Brion ◽  
Barry J. M. Gibb ◽  
Uta Wagner ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Glycogen Synthase ◽  
Tau Phosphorylation ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3Β

scholarly journals Effects of resveratrol and morin on insoluble tau in tau transgenic mice

2018 ◽  
Vol 9 (1) ◽  
pp. 54-60 ◽  
Author(s):  
Kwun Chung Yu ◽  
Ping Kwan ◽  
Stanley K.K. Cheung ◽  
Amy Ho ◽  
Larry Baum
Keyword(s):  
Transgenic Mice ◽  
Motor Function ◽  
Tau Protein ◽  
Late Stage ◽  
Animal Studies ◽  
Paired Helical Filaments ◽  
Hyperphosphorylated Tau ◽  
Total Tau ◽  
Tau Aggregation ◽  
Do So

Abstract Tauopathies are neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.

scholarly journals Dextran sulphate-induced tau assemblies cause endogenous tau aggregation and propagation in wild-type mice

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Masami Masuda-Suzukake ◽  
Genjiro Suzuki ◽  
Masato Hosokawa ◽  
Takashi Nonaka ◽  
Michel Goedert ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Guanidine Hydrochloride ◽  
Intracerebral Injection ◽  
Dextran Sulphate ◽  
Wild Type ◽  
Synthetic Filament ◽  
Biochemical Analyses ◽  
Tau Aggregation

Abstract Accumulation of assembled tau protein in the central nervous system is characteristic of Alzheimer’s disease and several other neurodegenerative diseases, called tauopathies. Recent studies have revealed that propagation of assembled tau is key to understanding the pathological mechanisms of these diseases. Mouse models of tau propagation are established by injecting human-derived tau seeds intracerebrally; nevertheless, these have a limitation in terms of regulation of availability. To date, no study has shown that synthetic assembled tau induce tau propagation in non-transgenic mice. Here we confirm that dextran sulphate, a sulphated glycosaminoglycan, induces the assembly of recombinant tau protein into filaments in vitro. As compared to tau filaments induced by heparin, those induced by dextran sulphate showed higher thioflavin T fluorescence and lower resistance to guanidine hydrochloride, which suggests that the two types of filaments have distinct conformational features. Unlike other synthetic filament seeds, intracerebral injection of dextran sulphate-induced assemblies of recombinant tau caused aggregation of endogenous murine tau in wild-type mice. AT8-positive tau was present at the injection site 1 month after injection, from where it spread to anatomically connected regions. Induced tau assemblies were also stained by anti-tau antibodies AT100, AT180, 12E8, PHF1, anti-pS396 and anti-pS422. They were thioflavin- and Gallyas-Braak silver-positive, indicative of amyloid. In biochemical analyses, accumulated sarkosyl-insoluble and hyperphosphorylated tau was observed in the injected mice. In conclusion, we revealed that intracerebral injection of synthetic full-length wild-type tau seeds prepared in the presence of dextran sulphate caused tau propagation in non-transgenic mice. These findings establish that propagation of tau assemblies does not require tau to be either mutant and/or overexpressed.

scholarly journals Modeling, Design Procedure and Control of a Low-Cost High-Gain Multi-Input Step-Up Converter

Electronics ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1424
Author(s):  
Edgardo Netzahuatl ◽  
Domingo Cortes ◽  
Marco A. Ramirez-Salinas ◽  
Jorge Resa ◽  
Leobardo Hernandez ◽  
...  
Keyword(s):  
Nonlinear Model ◽  
Low Cost ◽  
Renewable Energy Sources ◽  
Design Procedure ◽  
Input Voltage ◽  
High Gain ◽  
Grid Systems ◽  
Real Behavior ◽  
Different Characteristics ◽  
And Control

The use of several different sources to feed a load jointly is convenient in many applications, in particular those where two or more renewable energy sources are employed. These applications include energy harvesting, hybrid vehicles, and off-grid systems. A multi-input converter able to admit sources of different characteristics and select the output power of each source is necessary in such applications. Several topologies of multi-input converters have been proposed to this aim; however, most of them are controlled by simple strategies based on a small signal model of multi-input converters. In this work, a low cost high gain step-up multi-input converter is analyzed. A nonlinear model is derived. Using this model, a detailed design procedure is proposed. A 500 W converter prototype was constructed to confirm that the model predicted the real behavior of the converter. Using the nonlinear model, indirect voltage control of basic converters was extended to the multi-input converter. The obtained controller had a fast performance, and it was robust under load and input voltage variations. With the obtained model, the proposed design procedure, and the controller, a converter that was initially proposed for photovoltaic applications was enabled to be used in a broader range of applications. The herein exposed ideas for modeling, the design procedure, and control could be also applied to other multi-input converters.

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