Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation

Saito, Takashi; Mihira, Naomi; Matsuba, Yukio; Sasaguri, Hiroki; Hashimoto, Shoko; Narasimhan, Sneha; Zhang, Bin; Murayama, Shigeo; Higuchi, Makoto; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Saido, Takaomi C.

doi:10.1074/jbc.ra119.009487

Cited by 144 publications

(186 citation statements)

References 44 publications

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“…Although both models show cell-to-cell transfer of tau, thorough controls are required to exclude transgene leakage [198], viral diffusion throughout the brain [63] or side-effects related to tau overexpression. Regarding this latter, the recent humanization of the murine MAPT gene clearly indicates that prion-like propagation occurs without overexpression [151]. Many other in vivo models investigating tau propagation are based on intracranial delivery of pathological material (recombinant oligomeric or fibrillar tau, human or mouse brain-derived material, etc.)…”

Section: Tau Uptake/transfermentioning

confidence: 99%

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

et al. 2019

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The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.

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Section: Tau Uptake/transfermentioning

confidence: 99%

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

et al. 2019

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“…In the study of Vasconcelos et al, it has been shown that pre-aggregated Aβ can directly induce Tau fibrillization by cross-seeding in a cell-free assay and that Aβ-seeds can cross-seed Tau pathology and strongly catalyze pre-existing Tau-aggregation in a cellular Tau-aggregation experiment. All these results were successively confirmed by in vivo experiments and revealed the propagating potential of heterotopic seeding of filamentous Tau-aggregates induced by Aβ along functionally connected brain regions [77,79,81].…”

Section: Tau Proteinmentioning

confidence: 55%

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

et al. 2020

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Alzheimer’s disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions.

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“…AD-related tau pathology is particularly difficult to model, generally only occurring independently when non-physiological amounts of tau protein are overexpressed or when a point mutant version of tau is expressed, with the limitation that MAPT mutations do not cause AD 54 . Similarly, pre-tangle-like tau inclusions are only found following co-expression of familial AD-causing mutant human APP 54 , and not in double knock-in mice having both humanised APP and tau 56 . Instead, the Cyfip2 +/mouse model, which lacks one copy of an endogenous gene, rendering lower expression of CYFIP2 similar as that present in post-mortem AD brain 22 , shows stereotypical progression of phospho-tau accumulation 44,57 , and may therefore be a more physiological model of sporadic AD-related tau pathology.…”

Section: Discussionmentioning

confidence: 98%

“…For oligomeric Aβ1-42 treatments, aliquots were defrosted just prior to treatment, and diluted to a final concentration of 100 nM in cell culture medium, using equal volumes of HEPES buffer as control. The surface sensing of translation (SUnSET) assay was used to monitor protein synthesis in cell cultures, following a published protocol 56 . Briefly, puromycin (Sigma) was diluted to a final concentration of 10 μg/ml in culture medium for the last 10 minutes of the treatment.…”

Section: Pharmacological Treatmentsmentioning

confidence: 99%

Alzheimer’s disease-related dysregulation of protein synthesis causes key pathological features with ageing

Ghosh

Mizuno

Tiwari

et al. 2019

Preprint

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Alzheimer's disease (AD) is characterised by Aβ and tau pathology as well as synaptic degeneration. Recently, it was suggested that the development of these key disease features may at least in part be due to increased protein synthesis that is regulated by fragile X mental retardation protein (FMRP) and its binding partner CYFIP2. Using an unbiased screen, we show that exposure of primary neurons to Aβ increases FMRP-regulated protein synthesis and involves a reduction of CYFIP2 levels. Modelling this CYFIP2 reduction in mice, we find Aβ accumulation, development of pre-tangle tau pathology, gliosis, loss of synapses, and deficits in memory formation with ageing. We conclude that reducing endogenous CYFIP2 expression is sufficient to cause some key features of AD in mice. We therefore propose a central role for CYFIP2 in AD as a modulator of protein synthesis, highlighting a novel direction for therapeutic targeting.

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Humanization of the entire murine Mapt gene provides a murine model of pathological human tau propagation

Cited by 144 publications

References 44 publications

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

Alzheimer’s disease-related dysregulation of protein synthesis causes key pathological features with ageing

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