Tauopathies: new perspectives and challenges

Abstract

Background: Tauopathies are a class of neurodegenerative disorders characterized by neuronal and/or glial tau-positive inclusions.

Main body: Clinically, tauopathies can present with a range of phenotypes that include cognitive/behavioral-disorders, movement disorders, language disorders and non-specific amnestic symptoms in advanced age. Pathologically, tauopathies can be classified based on the predominant tau isoforms that are present in the inclusion bodies (i.e., 3R, 4R or equal 3R:4R ratio). Imaging, cerebrospinal fluid (CSF) and blood-based tau biomarkers have the potential to be used as a routine diagnostic strategy and in the evaluation of patients with tauopathies. As tauopathies are strongly linked neuropathologically and genetically to tau protein abnormalities, there is a growing interest in pursuing of tau-directed therapeutics for the disorders. Here we synthesize emerging lessons on tauopathies from clinical, pathological, genetic, and experimental studies toward a unified concept of these disorders that may accelerate the therapeutics.

Conclusions: Since tauopathies are still untreatable diseases, efforts have been made to depict clinical and pathological characteristics, identify biomarkers, elucidate underlying pathogenesis to achieve early diagnosis and develop disease-modifying therapies.

Keywords: Biomarkers; Genetics; Neurodegeneration; Tauopathies; Therapeutics.

Fig. 1

MAPT pathological mutations in exons, haplotypes, and alternative splicing. MAPT (microtubule associated protein tau) gene, located on chromosome 17q21.3, has been identified with over 100 mutations, and pathological mutations associated with increased risk for tauopathies are shown above. The difference between H1 and H2 haplotypes is a 900 kb inversion existing in the largest linkage disequilibrium (LD) area in chromosome 17. Besides, H1 and its various sub-haplotypes usually contribute to disease occurrence, while H2 haplotype often act as a protective factor. Alternative splicing is common in neuronal cells which help to increase genetic plasticity and the diversity of proteome under physiological conditions [6]. However, imbalance in the ratio of the 3R and 4R isoforms can give rise to the pathogenesis of tauopathies, as the 4R tau is more efficient in promoting microtubule assembly with an extra repeat domain R2 which hyper-stabilize MT and more free-floating tau leads to aggregates formation [3, 6, 7]

Fig. 2

Spatial–temporal distribution of tau lesions in schemes of brains. Deeper color means earlier involvement. A Tau progression in PiD has four stages, shown in medial and lateral views. Stage I, tau affects angular gyrus, limbic and frontotemporal regions. Stage II/III involves white matter tracts, subcortical structures (thalamus, striatum), serotonergic/noradrenergic brainstem nuclei, primary motor cortex and pre-cerebellar nuclei. Stage IV, tau invades visual cortex and cerebellar. Modified from [84]. B Tau progression in AD has six stages. Stage I/II, tau affect transentorhinal area. Stage III/IV, severe involvement of entorhinal, hippocampus and limbic areas happens. Stage V/VI, tau reaches primary and secondary neocortex. Modified from [85, 86]. C Tau progression in PSP has seven stages. Stage 0/I, pallido-luyso-nigral axis shows tau burden. Stage II/III, tau invades basal ganglia, dentate nucleus and pedunculopontine nucleus. Stage IV/V, tau reaches frontoparietal and temporal lobes. Stage VI/VII, occipital cortices, substantia nigra, subthalamic nucleus and globus pallidus are involved. Modified from [55]. D Tau progression in CTE has four stages, shown in coronal view at levels of genu of corpus callosum, mammillary body, and lateral geniculate body. Stage I/II, tau is restricted focally deep in the sulci of cortex, especially frontal lobe, surrounding small vessels and expand to superficial layers. Stage III, tau is widespread to cortices including frontal, temporal, parietal, and insular lobes. Meanwhile, amygdala, hippocampus, and entorhinal cortex are involved. Stage IV, tau affects most regions of cerebral cortex. Modified from [87]. E Tau progression (argyrophilic grains (AGs)) in AGD has four stages, shown in view same as D. Stage I is characterized by AGs in ambient gyrus, hippocampus (CA1), entorhinal and amygdala. Stage II shows involvement of medial temporal lobe and subiculum. Stage III, AGs reaches anterior temporal, cingulate gyrus, rectus gyrus, septum, accumbens nucleus, insular and orbitofrontal cortices, and hypothalamus (CA2 CA3). Stage IV involves neocortex and brainstem (not shown in figures). Modified from [63]

Fig. 3

Clinicopathological correlations of tauopathies. In the row listing clinical syndromes, combination of colors depicts the pathology composition within one phenotype. In the row listing neuropathology, different colors represent the classification of tauopathies based on tau isoforms primarily exist in aggregates. The solid lines connect pathologies and their frequently associated phenotypes, while dotted lines show infrequent associations. AD Alzheimer’s disease, aAD amnestic AD, PCA posterior cortical atrophy, lvPPA logopenic variant primary progressive aphasia, bvAD behavioral dysexecutive variant AD, CN cognitively normal, RS Richardson syndrome, P parkinsonism, PGF progressive gait freezing, CBS corticobasal syndrome, FTD frontotemporal dementia, bvFTD behaviour variant of frontotemporal dementia, nfvPPA non-fluent/agrammatic variant of primary progressive aphasia, svPPA Semantic variant of primary progressive aphasia, CTE chronic traumatic encephalopathy, PART primary age-related tauopathy, PiD Pick’s disease, AGD argyrophilic grain disease, CBD corticobasal degeneration, PSP progressive supranuclear palsy, GGT globular glial tauopathy

Fig. 4

Tau related therapies. Considering the pathogenic pathways existing in tauopathies, potential therapeutic methods include MAPT expression suppression, alternative splicing regulation, microtubule stabilization, post-translational modification adjustment, aggregation inhibition, tau clearance activation, and passive or active immunization. PPA phosphatase activator, P phosphate, Ac acetyl group, Gly O-linked N-acetylglucosamine (Gly) residues, PHF paired helical filament, NFTs neurofibrillary tangles, Ub ubiquitination; Created with BioRender.com.