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Tau Interacting Proteins: Gaining Insight into the Roles of Tau in Health and Disease

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Tau Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1184))

Abstract

Tau is most intensely studied in relation to its executive role in Tauopathies, a family of neurodegenerative disorders characterized by the accumulation of Tau aggregates [15, 21, 38, 75, 89, 111, 121, 135, 175, 176, 192]. Tau aggregation in the different Tauopathies differs in the affected cell type, the structure of aggregates and Tau isoform composition. However, in all Tauopathies, accumulation of pathological Tau in well-characterized and well-defined brain regions, correlates strongly with symptoms associated with the dysfunction of this brain region. Hence, symptoms of neurodegenerative Tauopathies can range from motoric to cognitive and behavioral symptoms, even extending to deterioration of vital functions when the disease progresses, or combinations of different symptoms governed by the affected brain regions. The most common Tauopathies are corticobasal degeneration (CBD), Pick’s disease, progressive supranuclear palsy (PSP) and frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17). However a growing number of diseases are characterized by Tau aggregation amounting to a large family of more than 20 disorders [176]. Most Tauopathies are sporadic, and are hence linked to a combination of environmental and genetic risk factors. However, mutations in MAPT have been identified which are autosomal dominantly linked to Tauopathies, including FTDP, PSP and CBD [94, 163, 185] (Alzforum, https://www.alzforum.org/mutations/mapt). More than 80 mutations have been identified in MAPT, both in intronic and exonic regions of the human MAPT. These mutations can be classified as missense mutations or splicing mutations. Most missense mutations cluster in or near the microtubule binding site of Tau, while most splicing mutations affect the splicing of exon 10 (encoding the R2 domain), and hence affect the 3R/4R ratio. While Alzheimer’s disease (AD), is the most prevalent Tauopathy, no mutations in MAPT associated with AD have been identified. Brains of AD patients are pathologically characterized by the combined presence of amyloid plaques and neurofibrillary tangles [171]. Familial forms of AD, termed early onset familial AD (EOFAD) with clinical mutations in APP or PS1/2, have an early onset, and are invariably characterized by the combined presence of amyloid and Tau pathology [24, 80, 170]. These EOFAD cases, identify a causal link between APP/PS1 misprocessing and the development of Tau pathology and neurodegeneration [80, 170]. Furthermore, combined genetic, pathological, biomarker and in vivo modelling data, indicate that amyloid pathology precedes Tau pathology, and support a role for Aβ as initiator and Tau as executor in the pathogenetic process of AD [80, 96, 97]. Hence, AD is often considered as a secondary Tauopathy (similar as for Down syndrome patients), in contrast to the primary Tauopathies described above. Tau aggregates in Tauopathies vary with respect to the ratio of different Tau isoforms (3R/4R), to the cell types displaying Tau aggregation and the structure of the aggregates. However, in all Tauopathies a strong correlation between progressive development of pathological Tau accumulation and the loss of the respective brain functions is observed.

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Authors and Affiliations

  1. BIOMED, Alzheimer Research Group, Hasselt University, Hasselt, Belgium

    Ilie-Cosmin Stancu, Dick Terwel & Ilse Dewachter

  2. Institute of Neuroscience, Catholic University of Louvain, Brussels, Belgium

    Mattia Ferraiolo & Ilse Dewachter

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  1. Ilie-Cosmin Stancu
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  2. Mattia Ferraiolo
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  3. Dick Terwel
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  4. Ilse Dewachter
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Correspondence to Ilse Dewachter .

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  1. Department of Life Sciences, Gakushuin University, Tokyo, Japan

    Akihiko Takashima

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Benjamin Wolozin

  3. University of Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France

    Luc Buee

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Stancu, IC., Ferraiolo, M., Terwel, D., Dewachter, I. (2019). Tau Interacting Proteins: Gaining Insight into the Roles of Tau in Health and Disease. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_13

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