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Review
. 2019 Feb 15;7(1):22.
doi: 10.1186/s40478-019-0664-z.

A walk through tau therapeutic strategies

Santosh Jadhav  1   2 , Jesus Avila  3   4 , Michael Schöll  5   6   7   8 , Gabor G Kovacs  9 , Enikö Kövari  10 , Rostislav Skrabana  2 , Lewis D Evans  11 , Eva Kontsekova  2 , Barbara Malawska  12 , Rohan de Silva  13 , Luc Buee  14 , Norbert Zilka  15
Affiliations
Review

A walk through tau therapeutic strategies

Santosh Jadhav et al. Acta Neuropathol Commun. .

Abstract

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease and related human tauopathies. There is a growing body of evidence indicating that pathological tau species can travel from cell to cell and spread the pathology through the brain. Throughout the last decade, physiological and pathological tau have become attractive targets for AD therapies. Several therapeutic approaches have been proposed, including the inhibition of protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, the inhibition of tau aggregation, active and passive immunotherapies, and tau silencing by antisense oligonucleotides. New tau therapeutics, across the board, have demonstrated the ability to prevent or reduce tau lesions and improve either cognitive or motor impairment in a variety of animal models developing neurofibrillary pathology. The most advanced strategy for the treatment of human tauopathies remains immunotherapy, which has already reached the clinical stage of drug development. Tau vaccines or humanised antibodies target a variety of tau species either in the intracellular or extracellular spaces. Some of them recognise the amino-terminus or carboxy-terminus, while others display binding abilities to the proline-rich area or microtubule binding domains. The main therapeutic foci in existing clinical trials are on Alzheimer's disease, progressive supranuclear palsy and non-fluent primary progressive aphasia. Tau therapy offers a new hope for the treatment of many fatal brain disorders. First efficacy data from clinical trials will be available by the end of this decade.

Keywords: Aggregation; Alzheimer’s disease; Immunotherapy; PET imaging; Tau vaccines; Tauopathies; Therapeutic interventions.

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Conflict of interest statement

Competing interests

SJ, RS, EK and NZ are Axon Neuroscience R&D Services employees. LB received research grants from UCB Biopharma. Other authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Yin and Yang of Tau protein
Fig. 2
Fig. 2
Tau pathologies in diverse tauopathies. Tau pathology in AD and PART comprise dystrophic neurites (a), axonal threads (b), pretangles (c) and NFTs (d). PSP is characterized by pretangles and threads (e), subcortical tangles (f), tufted astrocytes (g), and oligodendroglial coiled bodies (h). In CBD cases pretangles and threads (i), globose neuronal CBD-bodies (j), astrocytic plaques (k), and oligodendroglial coiled bodies (l) can be seen. AGD is characterized by 4R-tau positive neuronal dendritic grains (m), pretangles (n), granular/fuzzy astrocytes (o), and oligodendroglial coiled bodies (p). In GGT cases neuronal pretangles (q), spherical cytoplasmic inclusions (r), globular astroglial (s) and oligodendroglial (t) inclusions are detected. In Pick’s disease neuronal Pick bodies are frequent in the dentate gyrus (u) and show 3R immunoreactivity (v; here CA1 subregion is shown), furthermore, ramified astrocytes (w) and small globular oligodendroglial inclusions (x) can be noticed as well. Finally ARTAG comprises thorn shaped astrocytes and granular fuzzy astrocytes here demonstrated in the subependymal (y1), subpial (y2), perivascular (upper part of image 4) and white matter (lower part of image) (y3), and grey matter (y4) areas. All images show immunostaining for the AT8 antibody except (m) and (v) where immunostaining for 4R- and 3R-tau isoform, respectively, was performed. The bar in (a) represents 50 μm for a, e, f, g, h, l, m, t, u, v, y1, and y4; 35 μm for b, c, d, j, k, o, p, x; 30 μm for q and r; 40 μm for w and y2; 100 μm for i; 25 μm for s; and 150 μm for y3
Fig. 3
Fig. 3
Chemical structures of methylene blue derivatives
Fig. 4
Fig. 4
Multifunctional derivatives of piperazine
Fig. 5
Fig. 5
Structure of curcumin derivative PE859 dual tau and β-amyloid inhibitor
Fig. 6
Fig. 6
Structure of multifunctional carbazole–based cyanine compounds
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