What is the evidence that tau pathology spreads through prion-like propagation?

Abstract

Emerging experimental evidence suggests that the spread of tau pathology in the brain in Tauopathies reflects the propagation of abnormal tau species along neuroanatomically connected brain areas. This propagation could occur through a "prion-like" mechanism involving transfer of abnormal tau seeds from a "donor cell" to a "recipient cell" and recruitment of normal tau in the latter to generate new tau seeds. This review critically appraises the evidence that the spread of tau pathology occurs via such a "prion-like" mechanism and proposes a number of recommendations for directing future research. Recommendations for definitions of frequently used terms in the tau field are presented in an attempt to clarify and standardize interpretation of research findings. Molecular and cellular factors affecting tau aggregation are briefly reviewed, as are potential contributions of physiological and pathological post-translational modifications of tau. Additionally, the experimental evidence for tau seeding and "prion-like" propagation of tau aggregation that has emerged from cellular assays and in vivo models is discussed. Propagation of tau pathology using "prion-like" mechanisms is expected to incorporate several steps including cellular uptake, templated seeding, secretion and intercellular transfer through synaptic and non-synaptic pathways. The experimental findings supporting each of these steps are reviewed. The clinical validity of these experimental findings is then debated by considering the supportive or contradictory findings from patient samples. Further, the role of physiological tau release in this scenario is examined because emerging data shows that tau is secreted but the physiological function (if any) of this secretion in the context of propagation of pathological tau seeds is unclear. Bona fide prions exhibit specific properties, including transmission from cell to cell, tissue to tissue and organism to organism. The propagation of tau pathology has so far not been shown to exhibit all of these steps and how this influences the debate of whether or not abnormal tau species can propagate in a "prion-like" manner is discussed. The exact nature of tau seeds responsible for propagation of tau pathology in human tauopathies remains controversial; it might be tightly linked to the existence of tau strains stably propagating peculiar patterns of neuropathological lesions, corresponding to the different patterns seen in human tauopathies. That this is a property shared by all seed-competent tau conformers is not yet firmly established. Further investigation is also required to clarify the relationship between propagation of tau aggregates and tau-induced toxicity. Genetic variants identified as risks factors for tauopathies might play a role in propagation of tau pathology, but many more studies are needed to document this. The contribution of selective vulnerability of neuronal populations, as an alternative to prion-like mechanisms to explain spreading of tau pathology needs to be clarified. Learning from the prion field will be helpful to enhance our understanding of propagation of tau pathology. Finally, development of better models is expected to answer some of these key questions and allow for the testing of propagation-centred therapies.

Keywords: Alzheimer's disease; aggregation; prion-like propagation; seeding; tau; tauopathies; transmission.

Fig. 1

Human brain tau isoforms and the cores of tau filaments from Alzheimer’s disease. a MAPT and the six tau isoforms expressed in adult human brain. MAPT consists of 16 exons (E). Alternative mRNA splicing of E2 (red), E3 (green) and E10 (yellow) gives rise to the six tau isoforms (352–441 amino acids). The constitutively spliced exons (E1, E4, E5, E7, E9, E11, E12 and E13) are shown in blue. E0, which is part of the promoter, and E14 are noncoding (white). E6 and E8 (violet) are not transcribed in human brain. E4a (orange) is expressed only in the peripheral nervous system. The repeats (R1-R4) are shown, with three isoforms having four repeats each (4R) and three isoforms having three repeats each (3R). The core regions of the tau filaments from AD brain (V306-F378, using the numbering of the 441 amino acid tau isoform) are underlined. b, c Cross-sections of the cryogenic electron microscopy (cryo-EM) densities and atomic models of the cores of paired helical (b, in blue) and straight (c, in green) tau filaments. Each filament core consists of two identical protofilaments extending from V306-F378 of tau, which are arranged base-to-base (b) or back-to-base (c). The cryo-EM maps of the filament cores are at 3.4–3.5 Å resolution. Unsharpened, 4.5 Å low-pass filtered density is shown in grey. Density highlighted with an orange background is reminiscent of a less-ordered β-sheet and could accommodate an additional 16 amino acids, which would correspond to a mixture of residues 259–274 (R1) from 3R tau and residues 290–305 (R2) from 4R tau. Adapted from [46]

Fig. 2

Transcellular transfer of tau: potential mechanisms underpinning this process. Tau proteins can be transferred from donor cells (green) to recipient cells (orange) using different routes. This figure highlights different pathways reported (blue or violet arrows) or hypothesized (red arrows) in the literature. Whether these pathways are used for physiological transfer of tau proteins to subserve as yet unknown functions of normal tau, or are pathological routes for transfer of tau seeds that can propagate transcellular transfer of tau aggregation, remains to be resolved. Pathway indicated by blue arrows - tau proteins are released in the medium by extracellular vesicles like exosomes and ectosomes. It is unclear how tau proteins carried inside vesicles reach the cytoplasm of recipient cells (Q1). Violet pathway- Around 90% of tau in the extracellular space is found as free protein. The mechanism(s) by which tau reaches the extracellular space in free form is unknown. Passive diffusion facilitated by a membraneous transporter/receptor (Q2) or active exocytosis (Q3) might contribute to this process. Uptake of free tau species by recipient cells, including HSPG or APP-mediated endocytosis/ macropinocytosis of tau accumulates have been reported. Whether free or aggregated tau is taken up by other mechanisms such as diffusion (Q4) or non-receptor mediated endocytosis/macropinocytosis (Q5) has not been resolved. Nor is it known how membrane-bound tau can escape from vesicles and enter the cytoplasm of recipient cells (Q6). Orange pathway- Tau was shown to be present inside nanotubes connecting cells in vitro and to allow its interneuronal transfer. This mechanism could potentially participate in prion-like propagation of tau pathology but whether it is a mode of transcellular transfer of seeding-competent tau species in vivo needs to be investigated