Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice

Vogels, Thomas; Vargová, Gréta; Brezováková, Veronika; Quint, Wim H.; Hromádka, Tomáš

doi:10.3233/jad-200047

Cited by 11 publications

(13 citation statements)

References 53 publications

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“…Immunofluorescent histological staining was based on a modified version of a previously published protocol [79]. All steps were performed at room temperature unless mentioned otherwise.…”

Section: Methodsmentioning

confidence: 99%

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

Quint¹,

Matečko-Burmann

Schilcher

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) and other tauopathies are neurodegenerative disorders characterized by cellular accumulation of aggregated tau protein. Tau pathology within these disorders is accompanied by chronic neuroinflammation, such as activation of the classical complement pathway by complement initiation factor C1q. Additionally, about half of the AD cases present with inclusions composed of aggregated alpha-synuclein called Lewy bodies. Lewy bodies in disorders such as Parkinson’s disease and Lewy body dementia also frequently occur together with tau pathology. Immunotherapy is currently the most promising treatment strategy for tauopathies. However, the presence of multiple pathological processes within tauopathies makes it desirable to simultaneously target more than one disease pathway.MethodsHerein, we have developed three bispecific antibodies based on published antibody binding region sequences. One bispecific antibody binds to tau plus alpha-synuclein and two bispecific antibodies bind to tau plus C1q.ResultsThe affinity of the bispecific antibodies to their targets compared to their monospecific counterparts ranged from nearly identical to one order of magnitude lower. All bispecific antibodies retained binding to aggregated protein in patient-derived brain sections. The bispecific antibodies also retained their ability to inhibit aggregation of recombinant tau, regardless of whether the tau binding sites were in IgG or scFv format. Mono- and bispecific antibodies inhibited cellular seeding induced by AD-derived pathological tau with similar efficacy. Finally, both Tau-C1q bispecific antibodies completely inhibited the classical complement pathway.ConclusionBispecific antibodies that bind to multiple pathological targets may therefore present a promising approach to treat tauopathies and other neurodegenerative disorders.

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“…Immunofluorescent histological staining was based on a modified version of a previously published protocol [79]. All steps were performed at room temperature unless mentioned otherwise.…”

Section: Methodsmentioning

confidence: 99%

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

Quint¹,

Matečko-Burmann

Schilcher

et al. 2020

Preprint

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“…The collection of brain samples was performed as described previously [69]. An intraperitoneal administration of zolazepam/tiletamine (Zoletil 100, 100 mg/kg, Virbac) and xylazine (Xylariem, 20 mg/ml, Ecupharn N.V.) in a ratio of 1:1.7 was used to deeply anesthetize the mouse.…”

Section: Tissue Collection and Preparationmentioning

confidence: 99%

“…Immunohistochemistry was performed at room temperature as described previously [69]. Two hours of immersion in 4% PFA was used for post-fixation of the cryosections (40 µm).…”

Section: *Hybridoma Supernatant Immunohistochemistrymentioning

confidence: 99%

“…Here we describe an AAV-based model of astrocytic pathology that expresses human truncated tau(aa151-391/4R) and fluorophore mCherry under the astrocyte-specific GFAP promotor (AAV-GFAP-htTau). The truncated tau construct was previously shown to lead to mature neurofibrillary pathology, neuroinflammation, and associated functional deficits when expressed in neurons of mice and rats [69, 80, 81]. As tauopathies present with alterations in microglial function and neuroinflammation [68], we used AAV-GFAP-htTau to study the consequences of astrocytic tau pathology on microglial morphology.…”

Section: Introductionmentioning

confidence: 99%

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Astrocytic tau inclusions lead to microglial abnormalities, but leave neuronal networks intact

Vogels,

Vargová,

Hromádka

2024

Preprint

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Astrocytic tau inclusions are commonly found in the aging brain and primary tauopathies, such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). The functional consequences of these histopathological lesions, however, are unknown due to the lack of specific animal models. We have developed a mouse model of astrocytic tau pathology to study downstream effects on microglia and neuronal networks. We have designed an adeno-associated viral (AAV) vector expressing aggregation-prone human truncated tau (amino acids 151-391/4R) and red fluorophore mCherry in equal ratio under the astrocytic GFAP promotor. Injection of AAV-GFAP-htTau into the hippocampus of wild-type mice led to expression of human truncated tau in astrocytes and accumulation of soluble phosphorylated tau (p214, p231) but no detectable cognitive impairment. In vivo multiphoton imaging revealed alterations in microglial morphology in the vicinity of truncated tau positive astrocytes in the cortex. No alterations in firing patterns of excitatory cortical neurons surrounded by astrocytes overexpressing truncated tau were detected. These results suggest that early stages of astrocytic tau pathology lead to changes in microglial function, but not to functional impairment of neuronal networks.

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“…However, this was overcome by viral expression of non-mutated truncated human tau protein in the hippocampus of WT mice. This resulted in hyperphosphorylation of tau, accumulation of NFTs that also included mouse tau, and spread of human tau across the hippocampal circuit [ 105 ]. Whether this method induces tau filaments with a structure similar to AD remains to be determined.…”

Section: Animal Models Of Tau Propagationmentioning

confidence: 99%

Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

Robert

Schöll

Vogels

2021

IJMS

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Tauopathies are a heterogeneous class of neurodegenerative diseases characterized by intracellular inclusions of aggregated tau proteins. Tau aggregates in different tauopathies have distinct structural features and can be found in different cell types. Transgenic animal models overexpressing human tau have been used for over two decades in the research of tau pathology. However, these models poorly recapitulate the heterogeneity of tauopathies found in human brains. Recent findings demonstrate that injection of purified tau aggregates from the brains of human tauopathy patients recapitulates both the structural features and cell-type specificity of the tau pathology of the donor tauopathy. These models may therefore have unique translational value in the study of functional consequences of tau pathology, tau-based diagnostics, and tau targeting therapeutics. This review provides an update of the literature relating to seeding-based tauopathy and their potential applications.

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Viral Delivery of Non-Mutated Human Truncated Tau to Neurons Recapitulates Key Features of Human Tauopathy in Wild-Type Mice

Cited by 11 publications

References 53 publications

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

Bispecific tau antibodies with additional binding to C1q or alpha-synuclein

Astrocytic tau inclusions lead to microglial abnormalities, but leave neuronal networks intact

Tau Seeding Mouse Models with Patient Brain-Derived Aggregates

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