Highly specific and selective anti‐pS396‐tau antibody C10.2 targets seeding‐competent tau

Rosenqvist, Nina; Asuni, Ayodeji A.; Andersson, Christian R.; Christensen, Søren; Daechsel, Justus Alfred; Egebjerg, Jan; Falsig, Jeppe; Helboe, Lone; Jul, Pia; Kartberg, Fredrik; Pedersen, Lars Østergaard; Sigurdsson, Einar M.; Sotty, Florence; Skjødt, Karsten; Stavenhagen, Jeffrey B.; Volbracht, Christiane; Pedersen, Jan T.

doi:10.1016/j.trci.2018.09.005

Cited by 39 publications

(29 citation statements)

References 44 publications

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“…There has been significant progress in humanizing animal tauopathy models; by injecting patient-derived tau fibrils as seeds into rodent brains, the aggregation, histopathological lesions, and cell-type specificity of the patient can be recapitulated. Such models may provide better translatability to study the mechanisms of tau pathology in vivo and are increasingly used to test novel therapeutics (148,149). Important outstanding questions that can be studied with these models are, for example, how microglia, astrocytes, and other cell types are involved in the progression of tauopathy.…”

Section: Discussionmentioning

confidence: 99%

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

Vogels

Leuzy

Cicognola

et al. 2020

Biological Psychiatry

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Cellular accumulation of aggregated forms of the protein tau is a defining feature of so-called tauopathies such as Alzheimer's disease, progressive supranuclear palsy, and chronic traumatic encephalopathy. A growing body of literature suggests that conformational characteristics of tau filaments, along with regional vulnerability to tau pathology, account for the distinct histopathological morphologies, biochemical composition, and affected cell types seen across these disorders. In this review, we describe and discuss recent evidence from human postmortem and clinical biomarker studies addressing the differential vulnerability of brain areas to tau pathology, its cell-to-cell transmission, and characteristics of the different strains that tau aggregates can adopt. Cellular biosensor assays are increasingly used in human tissue to detect the earliest forms of tau pathology, before overt histopathological lesions (i.e., neurofibrillary tangles) are apparent. Animal models with localized tau expression are used to uncover the mechanisms that influence spreading of tau aggregates. Further, studies of human postmortem-derived tau filaments from different tauopathies injected in rodents have led to striking findings that recapitulate neuropathology-based staging of tau. Furthermore, the recent advent of tau positron emission tomography and novel fluid-based biomarkers render it possible to study the temporal progression of tau pathology in vivo. Ultimately, evidence from these approaches must be integrated to better understand the onset and progression of tau pathology across tauopathies. This will lead to improved methods for the detection and monitoring of disease progression and, hopefully, to the development and refinement of tau-based therapeutics.

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Section: Discussionmentioning

confidence: 99%

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

Vogels

Leuzy

Cicognola

et al. 2020

Biological Psychiatry

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“…There is consistent evidence that the transneuronal propagation of pathological Tau underlies the progression of Tauopathy in AD. Blocking Tau spreading using Tau antibodies therefore represents an attractive therapeutic strategy for AD, which is currently being pursued by several groups worldwide (Bright et al, 2015, Yanamandra et al, 2015, Albert et al, 2019, Rosenqvist et al, 2018, Vandermeeren et al, 2018). Here we demonstrate for the first time that in Tau K+100mM: 0.2431, veh: 0.7968; 2h: K+100mM: 0.7881, veh: 0.8917; 3h: K+100mM: 0.0592, veh: 0.1777; 4h: K+100mM: 0.5616, veh: 0.6041; 5h: K+100mM: 0.3720, veh: 0.7897; 6h: K+100mM: 0.8825, veh: 0.2753; 7h: K+100mM: 0.2564, veh: 0.2259 conv, 0.0629, cOFM, 0.9185;4h: conv, 0.0550, cOFM, 0.9847;6h: conv, 0.0651, cOFM, 0.1544;8h: conv, 0.1084, cOFM, 0.9581;10h: conv, 0.1460, cOFM, 0.8370;12h: conv, 0.4352, cOFM, 0.2087;14h: conv, 0.5078, cOFM, 0.3067;16h: conv, 0.7198, cOFM, 0.4510;18h: conv, 0.8739, cOFM, 0.6409;20h: conv, 0.1719, cOFM, 0.0892;22h: conv, 0.5585, cOFM, 0.2094;24h: conv, 0.5777, cOFM, 0 group, p-values.…”

Section: Discussionmentioning

confidence: 99%

Tau in the brain interstitial fluid is fragmented and seeding-competent

Barini

Plotzky

Mordashova

et al. 2020

Preprint

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In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells and notably, only a small fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that only a subset of Tau accounts for ISF seeding competence and have the potential to contribute to the propagation of Tau pathology.

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“…Because many tau kinases are involved in physiological intracellular signaling pathways, tau kinase inhibitor development appropriately avoiding physiological on targets might be difficult. Meanwhile, based on the view that a specific phosphorylation pattern is required to induce tau self-assembly (Fichou et al, 2019 ; Lauretti and Praticò, 2020 ), several groups have reported data indicating that the phospho-S396/404 epitope constitutes an effective therapeutic target (Boutajangout et al, 2011 ; Gu et al, 2013 ; Liu et al, 2016 ; Rosenqvist et al, 2018 ). Thus, studies have used immunotherapy targeting tau phosphorylation at S396/404.…”

Section: Tau-targeted Therapiesmentioning

confidence: 99%

“…The monoclonal antibody Lu AF87908 binds to the phospho-S396 region of tau (Sandusky-Beltran and Sigurdsson, 2020 ). A preclinical study showed that the original mouse antibody inhibited tau propagation induced by exposure of tau transgenic brain lysates in vivo and in vitro (Rosenqvist et al, 2018 ). Currently, a phase 1 trial (NCT04149860) is assessing the tolerability of Lu AF87908 in healthy individuals and AD patients (NCT04149860).…”

Section: Tau Clearance and Immunotherapymentioning

confidence: 99%

New Insights Into Drug Discovery Targeting Tau Protein

Soeda

Takashima

2020

Front. Mol. Neurosci.

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Microtubule-associated protein tau is characterized by the fact that it is an intrinsically disordered protein due to its lack of a stable conformation and high flexibility. Intracellular inclusions of fibrillar forms of tau with a β-sheet structure accumulate in the brain of patients with Alzheimer's disease and other tauopathies. Accordingly, detachment of tau from microtubules and transition of tau from a disordered state to an abnormally aggregated state are essential events preceding the onset of tau-related diseases. Many reports have shown that this transition is caused by post-translational modifications, including hyperphosphorylation and acetylation. The misfolded tau is self-assembled and forms a tau oligomer before the appearance of tau inclusions. Animal and pathological studies using human samples have demonstrated that tau oligomer formation contributes to neuronal loss. During the progression of tauopathies, tau seeds are released from cells and incorporated into other cells, leading to the propagation of pathological tau aggregation. Accumulating evidence suggests several potential approaches for blocking tau-mediated toxicity: (1) direct inhibition of pathological tau aggregation and (2) inhibition of tau post-translational modifications that occur prior to pathological tau aggregation, (3) inhibition of tau propagation and (4) stabilization of microtubules. In addition to traditional low-molecular-weight compounds, newer drug discovery approaches such as the development of medium-molecular-weight drugs (peptide- or oligonucleotide-based drugs) and high-molecular-weight drugs (antibody-based drugs) provide alternative pathways to preventing the formation of abnormal tau. Of particular interest are recent studies suggesting that tau droplet formation by liquid-liquid phase separation may be the initial step in aberrant tau aggregation, as well results that implicate roles for tau in dendritic and nuclear functions. Here, we review the mechanisms through which drugs can target tau and consider recent clinical trials for the treatment of tauopathies. In addition, we discuss the utility of these newer strategies and propose future directions for research on tau-targeted therapeutics.

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Highly specific and selective anti‐pS396‐tau antibody C10.2 targets seeding‐competent tau

Cited by 39 publications

References 44 publications

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

Tau in the brain interstitial fluid is fragmented and seeding-competent

New Insights Into Drug Discovery Targeting Tau Protein

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