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

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.

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

10.21203/rs.3.rs-889543/v2 ◽

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.

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

Brain Communications ◽

10.1093/braincomms/fcaa091 ◽

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.

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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 ◽

10.3390/ijms23020718 ◽

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.

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Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice

Frontiers in Neuroscience ◽

10.3389/fnins.2021.620176 ◽

2021 ◽

Vol 15 ◽

Author(s):

Yanmin Chang ◽

Yi Yao ◽

Rong Ma ◽

Zemin Wang ◽

Junjie Hu ◽

...

Keyword(s):

Transgenic Mice ◽

Cognitive Deficits ◽

Tau Protein ◽

Animal Studies ◽

Inflammatory Responses ◽

Hyperphosphorylated Tau ◽

Behavioral Deficits ◽

Synaptic Loss ◽

Underlying Mechanisms ◽

P301s Mutation

Alzheimer’s disease (AD) is a destructive and burdensome neurodegenerative disease, one of the most common characteristics of which are neurofibrillary tangles (NFTs) that are composed of abnormal tau protein. Animal studies have suggested that dl-3-n-butylphthalide (dl-NBP) alleviates cognitive impairment in mouse models of APP/PS1 and SAMP8. However, the underlying mechanisms related to this remain unclear. In this study, we examined the effects of dl-NBP on learning and memory in P301S transgenic mice, which carry the human tau gene with the P301S mutation. We found that dl-NBP supplementation effectively improved behavioral deficits and rescued synaptic loss in P301S tau transgenic mice, compared with vehicle-treated P301S mice. Furthermore, we also found that it markedly inhibited the hyperphosphorylated tau at the Ser262 site and decreased the activity of MARK4, which was associated with tau at the Ser262 site. Finally, dl-NBP treatment exerted anti-inflammatory effects and reduced inflammatory responses in P301S mice. In conclusion, our results provide evidence that dl-NBP has a promising potential for the therapy of tauopathies, including AD.

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Mbov_0503 Encodes a Novel Cytoadhesin that Facilitates Mycoplasma bovis Interaction with Tight Junctions

Microorganisms ◽

10.3390/microorganisms8020164 ◽

2020 ◽

Vol 8 (2) ◽

pp. 164 ◽

Cited By ~ 1

Author(s):

Xifang Zhu ◽

Yaqi Dong ◽

Eric Baranowski ◽

Xixi Li ◽

Gang Zhao ◽

...

Keyword(s):

Host Cell ◽

Tight Junctions ◽

Binding Capacity ◽

Host Cells ◽

Mycoplasma Bovis ◽

Knock Out ◽

Cell Monolayers ◽

Protein Levels ◽

Complex Process ◽

Host Cell Surface

Molecules contributing to microbial cytoadhesion are important virulence factors. In Mycoplasma bovis, a minimal bacterium but an important cattle pathogen, binding to host cells is emerging as a complex process involving a broad range of surface-exposed structures. Here, a new cytoadhesin of M. bovis was identified by producing a collection of individual knock-out mutants and evaluating their binding to embryonic bovine lung cells. The cytoadhesive-properties of this surface-exposed protein, which is encoded by Mbov_0503 in strain HB0801, were demonstrated at both the mycoplasma cell and protein levels using confocal microscopy and ELISA. Although Mbov_0503 disruption was only associated in M. bovis with a partial reduction of its binding capacity, this moderate effect was sufficient to affect M. bovis interaction with the host-cell tight junctions, and to reduce the translocation of this mycoplasma across epithelial cell monolayers. Besides demonstrating the capacity of M. bovis to disrupt tight junctions, these results identified novel properties associated with cytoadhesin that might contribute to virulence and host colonization. These findings provide new insights into the complex interplay taking place between wall-less mycoplasmas and the host-cell surface.

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The neuroprotective effect of the GSK-3β inhibitor and influence on the extrinsic apoptosis in the ALS transgenic mice

Journal of the Neurological Sciences ◽

10.1016/j.jns.2012.05.038 ◽

2012 ◽

Vol 320 (1-2) ◽

pp. 1-5 ◽

Cited By ~ 25

Author(s):

Suk-Won Ahn ◽

Jee-Eun Kim ◽

Kyung Seok Park ◽

Won-Jun Choi ◽

Yoon-Ho Hong ◽

...

Keyword(s):

Transgenic Mice ◽

Neuroprotective Effect ◽

Extrinsic Apoptosis ◽

Gsk 3Β

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

Translational Neuroscience ◽

10.1515/tnsci-2018-0010 ◽

2018 ◽

Vol 9 (1) ◽

pp. 54-60 ◽

Cited By ~ 8

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.

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S.24.03 Coexpression of FTDP-17 human tau and GSK-3β in transgenic mice synergistically act to induce tau polymerization and neurodegeneration

European Neuropsychopharmacology ◽

10.1016/s0924-977x(05)80692-3 ◽

2005 ◽

Vol 15 ◽

pp. S350

Keyword(s):

Transgenic Mice ◽

Gsk 3Β ◽

Tau Polymerization

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Transplantation of Adipose-Derived Stem Cells Alleviates Striatal Degeneration in a Transgenic Mouse Model for Multiple System Atrophy

Cell Transplantation ◽

10.1177/0963689720960185 ◽

2020 ◽

Vol 29 ◽

pp. 096368972096018

Author(s):

Christine Chang ◽

Jen-Wei Liu ◽

Bo Cheng Chen ◽

Zhe Sheng Jiang ◽

Chi Tang Tu ◽

...

Keyword(s):

Mouse Model ◽

Transgenic Mice ◽

Multiple System Atrophy ◽

Transgenic Mouse ◽

Neurodegenerative Disorder ◽

Ex Vivo ◽

Transgenic Mouse Model ◽

Intracerebral Injection ◽

Nigrostriatal Pathway ◽

Striatal Degeneration

Patients with multiple system atrophy (MSA), a progressive neurodegenerative disorder of adult onset, were found less than 9 years of life expectancy after onset. The disorders include bradykinesia and rigidity commonly seen in Parkinsonism disease and additional signs such as autonomic dysfunction, ataxia, or dementia. In clinical treatments, MSA poorly responds to levodopa, the drug used to remedy Parkinsonism disease. The exact cause of MSA is still unknown, and exploring a therapeutic solution to MSA remains critical. A transgenic mouse model was established to study the feasibility of human adipose-derived stem cell (ADSC) therapy in vivo. The human ADSCs were transplanted into the striatum of transgenic mice via intracerebral injection. As compared with sham control, we reported significantly enhanced rotarod performance of transgenic mice treated with ADSC at an effective dose, 2 × 105 ADSCs/mouse. Our ex vivo feasibility study supported that intracerebral transplantation of ADSC might alleviate striatal degeneration in MSA transgenic mouse model by improving the nigrostriatal pathway for dopamine, activating autophagy for α-synuclein clearance, decreasing inflammatory signal, and further cell apoptosis, improving myelination and cell survival at caudate-putamen.

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