Role of the Tau N-terminal region in microtubule stabilization revealed by newendogenous truncated forms

Derisbourg, Maxime; Leghay, Coline; Chiappetta, Giovanni; Fernandez-Gomez, Francisco-José; Laurent, Cyril; Demeyer, Dominique; Carrier, Sébastien; Buée‐Scherrer, Valérie; Blum, David; Vinh, Joëlle; Sergeant, Nicolas; Verdier, Yann; Buée, Luc; Hamdane, Malika

doi:10.1038/srep09659

Cited by 106 publications

(75 citation statements)

References 59 publications

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“…This limitation of our model has been unavoidable, as N-terminal tau cleavage sites are yet poorly characterized, and only few N-terminal cleavage sites, located at the beginning of the acidic region of tau, have been confirmed in situ . 18, 64, 65 …”

Section: Discussionmentioning

confidence: 99%

Co-expression of truncated and full-length tau induces severe neurotoxicity

et al. 2016

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Abundant tau inclusions are a defining hallmark of several human neurodegenerative diseases, including Alzheimer's disease. Protein fragmentation is a widely observed event in neurodegenerative proteinopathies. The relevance of tau fragmentation for the neurodegenerative process in tauopathies has yet remained unclear. Here we found that co-expression of truncated and full-length human tau in mice provoked the formation of soluble high-molecular-weight tau, the failure of axonal transport, clumping of mitochondria, disruption of the Golgi apparatus and missorting of synaptic proteins. This was associated with extensive nerve cell dysfunction and severe paralysis by the age of 3 weeks. When the expression of truncated tau was halted, most mice recovered behaviorally and functionally. In contrast, co-expression of full-length tau isoforms did not result in paralysis. Truncated tau thus induces extensive but reversible neurotoxicity in the presence of full-length tau through the formation of nonfilamentous high-molecular-weight tau aggregates, in the absence of tau filaments. Targeting tau fragmentation may provide a novel approach for the treatment of human tauopathies.

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Section: Discussionmentioning

confidence: 99%

Co-expression of truncated and full-length tau induces severe neurotoxicity

et al. 2016

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“…To the best of our knowledge, this is the first examination of a DNA tau vaccine. We chose to target amino acids 2–18 of the tau N-terminus as a B cell epitope based on data showing that this region, comprising phosphatase-activating domain (PAD), (i) plays an important role in activation of a signaling cascade that leads to inhibition of anterograde fast axonal transport (FAT)[28–31]; (ii) is normally hidden in microtubule bound tau conformations but becomes highly exposed during tau aggregation[28, 29]; and (iii) plays an important role in polymerization of tau, and truncation or phosphorylation of this region may have a neuroprotective role[30, 32]. In this report, THY-Tau22 mice immunized with AV-1980D generated very high titers of anti-tau antibodies that recognized tangles in human AD brain tissue and reduced the accumulation of total tau in the brains of vaccinated mice.…”

Section: Introductionmentioning

confidence: 99%

MultiTEP platform-based DNA epitope vaccine targeting N-terminus of tau induces strong immune responses and reduces tau pathology in THY-Tau22 mice

Davtyan

Chen

Zagorski

et al. 2017

Vaccine

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Background By the time clinical symptoms of Alzheimer’s disease (AD) manifest in patients there is already substantial tau pathology in the brain. Recent evidence also suggests that tau pathology can become self-propagating, further accelerating disease progression. Over the last decade several groups have tested the efficacy of protein-based anti-tau immunotherapeutics in various animal models of tauopathy. Here we report on the immunological and therapeutic potency of the first anti-tau DNA vaccine based on the MultiTEP platform, AV-1980D, in THY-Tau22 transgenic mice. Methods Starting at 3 months of age, m,ice were immunized intramuscularly with AV-1980D vaccine targeting a tau B cell epitope spanning aa2–18 followed by electroporation (EP). Humoral and cellular immune responses in vaccinated animals were analyzed by ELISA and ELISpot, respectively. Neuropathological changes in the brains of experimental and control mice were then analyzed by biochemical (WB and ELISA) and immunohistochemical (IHC) methods at 9 months of age. Results EP-mediated AV-1980D vaccinations of THY-Tau22 mice induced activation of Th cells specific to the MultiTEP vaccine platform and triggered robust humoral immunity response specific to tau. Importantly, no activation of potentially harmful autoreactive Th cell responses specific to endogenous tau species was detected. The maximum titers of anti-tau antibodies were reached after two immunizations and remained slightly lower, but steady during five subsequent monthly immunizations. Vaccinations with AV-1980D followed by EP significantly reduced total tau and pS199 and AT180 phosphorylated tau levels in the brains extracts of vaccinated mice, but produced on subtle non-significant effects on other phosphorylated tau species. Conclusions These data demonstrate that MultiTEP-based DNA epitope vaccination targeting the N-terminus of tau is highly immunogenic and therapeutically potent in the THY-Tau22 mouse model of tauopathy and indicate that EP-mediated DNA immunization is an attractive alternative to protein-based adjuvanted vaccines for inducing high concentrations of anti-tau antibodies.

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“…, 2014), generate products that show increased release from neurons (Kanmert et al. , 2015), or produce fragments with a modified MT interaction (Derisbourg et al. , 2015).…”

Section: Introductionmentioning

confidence: 99%