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Cellular and regional vulnerability in frontotemporal tauopathies

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Abstract

The frontotemporal tauopathies all deposit abnormal tau protein aggregates, but often of only certain isoforms and in distinguishing pathologies of five main types (neuronal Pick bodies, neurofibrillary tangles, astrocytic plaques, tufted astrocytes, globular glial inclusions and argyrophilic grains). In those with isoform specific tau aggregates glial pathologies are substantial, even though there is limited evidence that these cells normally produce tau protein. This review will assess the differentiating features and clinicopathological correlations of the frontotemporal tauopathies, the genetic predisposition for these different pathologies, their neuroanatomical selectivity, current observations on how they spread through the brain, and any potential contributing cellular and molecular changes. The findings show that diverse clinical phenotypes relate most to the brain region degenerating rather than the type of pathology involved, that different regions on the MAPT gene and novel risk genes are associated with specific tau pathologies, that the 4-repeat glial tauopathies do not follow individual patterns of spreading as identified for neuronal pathologies, and that genetic and pathological data indicate that neuroinflammatory mechanisms are involved. Each pathological frontotemporal tauopathy subtype with their distinct pathological features differ substantially in the cell type affected, morphology, biochemical and anatomical distribution of inclusions, a fundamental concept central to future success in understanding the disease mechanisms required for developing therapeutic interventions. Tau directed therapies targeting genetic mechanisms, tau aggregation and pathological spread are being trialled, although biomarkers that differentiate these diseases are required. Suggested areas of future research to address the regional and cellular vulnerabilities in frontotemporal tauopathies are discussed.

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Acknowledgements

The authors wish to thank Ms Heidi Cartwright for assistance with preparation of figures and the staff of the Sydney Brain Bank (supported by the University of New South Wales and Neuroscience Research Australia) and the NSW Brain Tissue Resource Centre (supported by the National Institute on Alcohol Abuse and Alcoholism, NIHR28AA012725) for initial characterisation of the cases used to prepare the sections for the figurework. We also thank Dr Janet Van Eersel and Professor Lars Ittner from the Dementia Research Centre, Macquarie University, for providing the tau western blot used in Fig. 4.

Funding

This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from NHMRC of Australia program grants (#1132524). GH is a NHMRC Senior Principal Research Fellow (#1079679).

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  1. Charles Perkins Centre and Discipline of Pathology, Faculty of Medicine and Health, University of Sydney, Sydney, Australia

    Shelley L. Forrest & Jillian J. Kril

  2. Brain and Mind Centre and Central Clinical School, Faculty of Medicine and Health, University of Sydney, 94 Mallet Street, Camperdown, Sydney, NSW, 2050, Australia

    Glenda M. Halliday

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Forrest, S.L., Kril, J.J. & Halliday, G.M. Cellular and regional vulnerability in frontotemporal tauopathies. Acta Neuropathol 138, 705–727 (2019). https://doi.org/10.1007/s00401-019-02035-7

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