Tau neurotoxicity and rescue in animal models of human Tauopathies

Krüger, Lars; Mandelkow, E.

doi:10.1016/j.conb.2015.09.004

Cited by 52 publications

(37 citation statements)

References 76 publications

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“…Historically, there has been a debate as to which tau protein species is the most toxic to cells – whether monomers, oligomers, PHF or NFT [41], [42]. Recent attempts to address this question have also sought to understand if tau toxicity and pathology spread in a prion-like manner.…”

Section: Discussionmentioning

confidence: 99%

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

Karikari

Turner

Stass

et al. 2017

Protein Expression and Purification

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Recombinant tau protein is widely used to study the biochemical, cellular and pathological aspects of tauopathies, including Alzheimer's disease and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTPD-17). Pure tau in high yield is a requirement for in vitro evaluation of the protein's physiological and toxic functions. However, the preparation of recombinant tau is complicated by the protein's propensity to aggregate and form truncation products, necessitating the use of multiple, time-consuming purification methods. In this study, we investigated parameters that influence the expression of wild type and FTPD-17 pathogenic tau, in an attempt to identify ways to maximise expression yield. Here, we report on the influence of the choice of host strain, induction temperature, duration of induction, and media supplementation with glucose on tau expression in Escherichia coli. We also describe a straightforward process to purify the expressed tau proteins using immobilised metal affinity chromatography, with favourable yields over previous reports. An advantage of the described method is that it enables high yield production of functional oligomeric and monomeric tau, both of which can be used to study the biochemical, physiological and toxic properties of the protein.

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Section: Discussionmentioning

confidence: 99%

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

Karikari

Turner

Stass

et al. 2017

Protein Expression and Purification

View full text Add to dashboard Cite

show abstract

“…Recent work using a variety of animal and cellular models [25] has begun to tease out the complexities of taumediated stress and injury but has also revealed both the promise and perils of relying on such mice for clarifying the role of tau in human pathogenesis. Most mouse models are based on the P301 L and P301S mutations of MAPT.…”

Section: Tau Pathogenesismentioning

confidence: 99%

Tau: From research to clinical development

Holtzman

Carrillo

Hendrix

et al. 2016

Alzheimer's & Dementia

122

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Alzheimer's Association Research Roundtable Fall 2015-Tau: From research to clinical development. Tau pathology is recognized as the key driver of disease progression in Alzheimer's and other neurodegenerative diseases. Although this makes tau an attractive target for the development of novel diagnostic and therapeutic strategies, the mechanisms underlying the onset and progression of tau-related neurotoxicity remain elusive. Recent strides in the development of sophisticated preclinical models and the emergence of tau PET imaging and fluid biomarkers provide new opportunities to increase our understanding of tau biology, overcome translational challenges, and accelerate the advancement of tau therapeutics from bench to bedside. With this in mind, the Alzheimer's Association convened a Research Roundtable in October 2015, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of tau pathogenic pathways and review the evolution of tau therapeutics and biomarkers currently in development. The meeting provided a forum to share experience and expertise with the common goal of advancing the discovery and development of new treatment strategies and expediting the design and implementation of efficient clinical trials.

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“…The contribution of the Tau gene specifically to sporadic cases of AD may not be outstanding, in contrast to the ApoE gene (Piaceri et al, 2013). Nonetheless, the biological pathway involving the Tau protein plays a central role in AD pathology (Krüger and Mandelkow, 2015). Likewise, the potential value of the DISC1 protein as a “biological” lead in understanding molecular mechanisms for major mental illnesses is now appreciated.…”

Section: Introductionmentioning

confidence: 99%

Utility and validity of DISC1 mouse models in biological psychiatry

et al. 2016

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We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10–15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future.

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Tau neurotoxicity and rescue in animal models of human Tauopathies

Cited by 52 publications

References 76 publications

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

Expression and purification of tau protein and its frontotemporal dementia variants using a cleavable histidine tag

Tau: From research to clinical development

Utility and validity of DISC1 mouse models in biological psychiatry

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