Characterization of TauC3 antibody and demonstration of its potential to block tau propagation

Nicholls, Samantha B.; DeVos, Sarah L.; Commins, Caitlin; Nobuhara, Chloe K.; Bennett, Rachel E.; Corjuc, Diana L.; Maury, Eduardo A.; Eftekharzadeh, Bahareh; Akingbade, Ololade; Fan, Zhanyun; Roe, Allyson D.; Takeda, Shuko; Wegmann, Susanne; Hyman, Bradley T.

doi:10.1371/journal.pone.0177914

Cited by 42 publications

(28 citation statements)

References 21 publications

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“…The presence of tau seeding as measured using the tau Tau RD -P301S-CFP/YFP in vitro biosensor (Holmes et al, 2014 ) has previously shown an association with the presence of tau pathology, both in tau transgenic mice (Holmes et al, 2014 ; DeVos et al, 2017 ) and in human brains (Furman et al, 2017 ; Nicholls et al, 2017 ; Nobuhara et al, 2017 ). Interestingly, tau seeding has also been reported in tissues—both in mice and in human brain lysate—where overt tau pathology has not yet developed or is rare (Holmes et al, 2014 ; Furman et al, 2017 ), suggesting that some amount of tau aggregates exist in a brain region before they accumulate to a point of filling the neuronal somatodendritic compartment and are abundantly detected by tau IHC.…”

Section: Resultsmentioning

confidence: 99%

“…In keeping with the idea that tau aggregates move across synapses, one possible treatment is tau immunotherapy—as tau aggregates are released from a neuron, the aggregates can be captured by an antibody and cleared before they can be taken up by the adjoining neuron. This therapy has been shown both in vitro and in vivo to be successful at preventing both tau pathology formation and propagation (Boimel et al, 2010 ; Bi et al, 2011 ; Yanamandra et al, 2013 ; Castillo-Carranza et al, 2014 ; Ittner et al, 2015 ; Nicholls et al, 2017 ; Nobuhara et al, 2017 ). Based on these successful studies, tau immunotherapy has been taken to the human clinic by multiple groups for those with early AD (NCT02880956, NCT03289143, NCT03056729).…”

Section: Discussionmentioning

confidence: 99%

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Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

et al. 2018

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Alzheimer's disease (AD) is defined by the presence of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau aggregates as well as extracellular amyloid-beta plaques. The presence and spread of tau pathology through the brain is classified by Braak stages and thought to correlate with the progression of AD. Several in vitro and in vivo studies have examined the ability of tau pathology to move from one neuron to the next, suggesting a “prion-like” spread of tau aggregates may be an underlying cause of Braak tau staging in AD. Using the HEK293 TauRD-P301S-CFP/YFP expressing biosensor cells as a highly sensitive and specific tool to identify the presence of seed competent aggregated tau in brain lysate—i.e., tau aggregates that are capable of recruiting and misfolding monomeric tau—, we detected substantial tau seeding levels in the entorhinal cortex from human cases with only very rare NFTs, suggesting that soluble tau aggregates can exist prior to the development of overt tau pathology. We next looked at tau seeding levels in human brains of varying Braak stages along six regions of the Braak Tau Pathway. Tau seeding levels were detected not only in the brain regions impacted by pathology, but also in the subsequent non-pathology containing region along the Braak pathway. These data imply that pathogenic tau aggregates precede overt tau pathology in a manner that is consistent with transneuronal spread of tau aggregates. We then detected tau seeding in frontal white matter tracts and the optic nerve, two brain regions comprised of axons that contain little to no neuronal cell bodies, implying that tau aggregates can indeed traverse along axons. Finally, we isolated cytosolic and synaptosome fractions along the Braak Tau Pathway from brains of varying Braak stages. Phosphorylated and seed competent tau was significantly enriched in the synaptic fraction of brain regions that did not have extensive cellular tau pathology, further suggesting that aggregated tau seeds move through the human brain along synaptically connected neurons. Together, these data provide further evidence that the spread of tau aggregates through the human brain along synaptically connected networks results in the pathogenesis of human Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

et al. 2018

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“…Proposed mechanisms for tau immunotherapies are epitope, affinity, conformation, and aggregate size dependent. Studies of specific tau immunotherapies have demonstrated that either extracellular ( Yanamandra et al., 2013 ) or intracellular ( Gu et al., 2013 , Nicholls et al., 2017 ) tau can be targeted. Antibodies are thought to halt the progression of disease by binding to tau aggregates, triggering their uptake and clearance via either endosomal or proteasome pathways ( Chai et al., 2011 , Gu et al., 2013 , Mallery et al., 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

et al. 2018

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SummaryIn Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.

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“…The tau propagation hypothesis, based on the concept that the clinical progression of AD is linked with the spreading of the tau pathology, supports the idea that clearing the tau involved in propagation may slow the spread of the tau pathology and possibly of cognitive decline (Nicholls et al, 2017;Nobuhara et al, 2017). The potential efficacy of antibodybased therapeutics targeting tau has been demonstrated in several studies using animal models Pedersen and Sigurdsson, 2015), although it is unclear how an antibody can exert its therapeutic efficacy against an intracellular protein such as tau.…”

Section: Future Directions: Toward Diagnosis and Treatment Based On Tmentioning

confidence: 96%

Tau Propagation as a Diagnostic and Therapeutic Target for Dementia: Potentials and Unanswered Questions

Takeda

2019

Front. Neurosci.

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A unique clinical course of Alzheimer's disease (AD), beginning with memory deficit as the earliest symptom, is well-correlated with a progressive pattern of intracellular aggregates of tau (neurofibrillary tangles), which spread from the medial temporal lobe to other brain areas in a stereotypical manner. Recent findings from basic research using in vitro and in vivo models demonstrated that pathological forms of extracellular tau can be taken up by cells and induce intracellular tau aggregates. On the basis of these neuropathological observations and experimental findings, the "tau propagation hypothesis" has been proposed, in which the stereotypical spreading of the tau pathology observed in the brain of AD patients can be explained by the interneuron transfer of the pathological form of tau. The concept of tau propagation remains controversial, and many unsolved questions exist; however, it has been attracting attention as a potential therapeutic target for halting AD progression. This article reviews the recent findings regarding the tau propagation hypothesis, including the basic concept and evidence of interneuron tau transfer, potentials as a diagnostic and therapeutic target, and unsolved questions for a better understanding of tau propagation.

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Characterization of TauC3 antibody and demonstration of its potential to block tau propagation

Cited by 42 publications

References 21 publications

Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

Synaptic Tau Seeding Precedes Tau Pathology in Human Alzheimer's Disease Brain

Extracellular Monomeric and Aggregated Tau Efficiently Enter Human Neurons through Overlapping but Distinct Pathways

Tau Propagation as a Diagnostic and Therapeutic Target for Dementia: Potentials and Unanswered Questions

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