Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Limorenko, Galina; Lashuel, Hilal A.

doi:10.1039/d1cs00127b

Cited by 93 publications

(87 citation statements)

References 600 publications

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“…Accordingly, we propose that Stg/Cdc25 comprise novel Tau phosphatases with strong impact on Tau biology and pathology, whose activity deserves further studies. Thus, Stg/Cdc25 adds to the list of key Tau regulators like Shaggy/GSK3-B (Jackson et al, 2002), Par-1/MARK (Ambegaokar and Jackson, 2011; Nishimura et al, 2004), MAPK and PP2A phosphatases (Shulman and Feany, 2003) identified in flies (reviewed in (Gistelinck et al, 2012; Hannan et al, 2016; Limorenko and Lashuel, 2022b).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in MAPT, the Tau encoding gene, and post-translational modifications (PTM), including phosphorylation, acetylation and ubiquitination, are the most common alterations associated with Tau pathology (Limorenko and Lashuel, 2022a; Tapia-Rojas et al, 2019). Recently, cryo-EM studies showed that cross-talk between PTMs underlies Tau structural diversity, impacts on fibril structure and correlates with distinctive tauopathies (Arakhamia et al, 2020; Fitzpatrick et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

“…Drosophila tauopathy models have been successfully used to uncover Tau interactors and investigate the molecular basis of Tau pathogenesis (Limorenko and Lashuel, 2022b). Pan-neuronal expression of wild-type or mutated human Tau (hTau) isoforms in flies recapitulates key pathological features of human tauopathies, including accumulation of abnormally phosphorylated forms of Tau, neuronal loss, progressive motor deficits and neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration

Oliveira

Santos

Pinho

et al. 2022

Preprint

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Tau pathology is defined by the intracellular accumulation of abnormally phosphorylated Tau and is prevalent in several neurodegenerative disorders. The identification of modulators of Tau abnormal phosphorylation and aggregation is key to understand disease progression and develop targeted therapeutic approaches. In this study we identify String/Cdc25 phosphatase as a suppressor of Tau abnormal phosphorylation and associated toxicity. Using a Drosophila model of tauopathy we show that Tau dephosphorylation by Stg/Cdc25 correlates with reduced Tau oligomerization, brain vacuolization and locomotor deficits in flies. Moreover, using a disease mimetic model, we provide evidence that Stg/Cdc25 reduces Tau phosphorylation levels independently of Tau aggregation status and delays neurodegeneration progression in the fly. These findings uncover a role for Stg/Cdc25 phosphatases as regulators of Tau biology, that extends beyond their well-characterized function as cell-cycle regulators during cell proliferation, and point-out Stg/Cdc25 based approaches as promising entry points to target abnormal Tau phosphorylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration

Oliveira

Santos

Pinho

et al. 2022

Preprint

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“…Early diagnosis, early detection, and early intervention are a significant and effective strategy [ 1 , 2 ]. The tau protein, as a defining characteristic of AD, is recognized as an important biomarker of AD [ 3 , 4 ]. The quantitative determination of the tau protein in cerebrospinal fluid (CSF) is the gold standard for the diagnosis of AD.…”

Section: Introductionmentioning

confidence: 99%

Portable Vertical Graphene@Au-Based Electrochemical Aptasensing Platform for Point-of-Care Testing of Tau Protein in the Blood

Liu

et al. 2022

Biosensors

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Alzheimer’s disease (AD) is a long-term neurodegenerative disease that poses a serious threat to human life and health. It is very important to develop a portable quantitative device for AD diagnosis and personal healthcare. Herein, we develop a portable electrochemical sensing platform for the point-of-care detection of AD biomarkers in the blood. Such a portable platform integrates nanoAu-modified vertical graphene (VG@Au) into a working electrode, which can significantly improve sensitivity and reduce detection limit due to the large specific surface, excellent electrical conductivity, high stability, and good biocompatibility. The tau protein, as an important factor in the course of AD, is selected as a key AD biomarker. The results show that the linear range of this sensing platform is 0.1 pg/mL to 1 ng/mL, with a detection limit of 0.034 pg/mL (S/N = 3), indicating that this portable sensing platform meets the demand for the detection of the tau protein in the blood. This work offers great potential for AD diagnosis and personal healthcare.

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Integrated Ultrasound‐Enrichment and Machine Learning in Colorimetric Lateral Flow Assay for Accurate and Sensitive Clinical Alzheimer's Biomarker Diagnosis

Wang,

Zhu,

Zhou

et al. 2024

Advanced Science

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The colloidal gold nanoparticle (AuNP)‐based colorimetric lateral flow assay (LFA) is one of the most promising analytical tools for point‐of‐care disease diagnosis. However, the low sensitivity and insufficient accuracy still limit its clinical application. In this work, a machine learning (ML)‐optimized colorimetric LFA with ultrasound enrichment is developed to achieve the sensitive and accurate detection of tau proteins for early screening of Alzheimer's disease (AD). The LFA device is integrated with a portable ultrasonic actuator to rapidly enrich microparticles using ultrasound, which is essential for sample pre‐enrichment to improve the sensitivity, followed by ML algorithms to classify and predict the enhanced colorimetric signals. The results of the undiluted serum sample testing show that the protocol enables efficient classification and accurate quantification of the AD biomarker tau protein concentration with an average classification accuracy of 98.11% and an average prediction accuracy of 99.99%, achieving a limit of detection (LOD) as sensitive as 10.30 pg mL−1. Further point‐of‐care testing (POCT) of human plasma samples demonstrates the potential use of LFA in clinical trials. Such a reliable lateral flow immunosensor with high precision and superb sensing performance is expected to put LFA in perspective as an AD clinical diagnostic platform.

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Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

Abstract: We discuss novel approaches for embracing and reproducing complexity of Tau pathology required for developing disease-relevant diagnostics and effective therapies.

Cited by 93 publications

References 600 publications

String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration

String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration

Portable Vertical Graphene@Au-Based Electrochemical Aptasensing Platform for Point-of-Care Testing of Tau Protein in the Blood

Integrated Ultrasound‐Enrichment and Machine Learning in Colorimetric Lateral Flow Assay for Accurate and Sensitive Clinical Alzheimer's Biomarker Diagnosis

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