Fate and propagation of endogenously formed Tau aggregates in neuronal cells

Abstract

Tau accumulation in the form of neurofibrillary tangles in the brain is a hallmark of tauopathies such as Alzheimer's disease (AD). Tau aggregates accumulate in brain regions in a defined spatiotemporal pattern and may induce the aggregation of native Tau in a prion-like manner. However, the underlying mechanisms of cell-to-cell spreading of Tau pathology are unknown and could involve encapsulation within exosomes, trans-synaptic passage, and tunneling nanotubes (TNTs). We have established a neuronal cell model to monitor both internalization of externally added fibrils, synthetic (K18) or Tau from AD brain extracts, and real-time conversion of microtubule-binding domain of Tau fused to a fluorescent marker into aggregates. We found that these endogenously formed deposits colabel with ubiquitin and p62 but are not recruited to macroautophagosomes, eventually escaping clearance. Furthermore, endogenous K18-seeded Tau aggregates spread to neighboring cells where they seed new deposits. Transfer of Tau aggregates depends on direct cell contact, and they are found inside TNTs connecting neuronal cells. We further demonstrate that contact-dependent transfer occurs in primary neurons and between neurons and astrocytes in organotypic cultures.

α-Synuclein fibrils subvert lysosome structure and function for the propagation of protein misfolding between cells through tunneling nanotubes

“…Interestingly, our results show that lysosomes containing α-syn fibrils are not targeted for lysophagy [84] (S4 Fig), possibly suggesting a rescue mechanism such as the one orchestrated by the endosomal sorting complexes required for transport (ESCRT) machinery [111,112]. Considering the evidence supporting autophagy impairment in NDs and more specifically following α-syn accumulation [55,113], and the recent findings that impaired autophagic flux contributes to the occurrence of LMP [114], it will be interesting to assess the contribution of autophagy to LMP, lysosomal dysfunction, and propagation of α-syn.…”

“…TNTs are openended structures [48,49] that allow the exchange of various cargos, including entire organelles, such as mitochondria and lysosomes, between cells [19,[37][38][39][40]. In addition to α-syn fibrils, other amyloidogenic proteins such as prion protein [50][51][52], huntingtin [53], and tau [52,54,55] use TNTs as highways for transfer to naive cells, suggesting that TNTs are common routes for the spread of pathogenic proteins between cells. Of particular interest, we showed that α-syn fibrils can be efficiently transferred between neuronal Cath.a-differentiated (CAD) cells, primary neurons, primary astrocytes, and human neural progenitor cells and between organotypic hippocampal slices and astrocytes.…”

Peering into tunneling nanotubes—The path forward

“…Meanwhile, we and others have shown that extracellular monomeric and fibrillar Tau species induce the formation of TNTs, which facilitate their transfer between neuronal cells (Tardivel et al , 2016; Abounit et al , 2016b). We have also recently shown that endogenously formed Tau aggregates are found in TNTs (Chastagner et al , 2020). Together, these data indicate that proteins involved in Tauopathies and AD could hijack TNTs and use them as a means of spread, as previously described for Prion, α‐syn, and mHTT (Victoria & Zurzolo, 2017).…”

Exosomal and vesicle‐free tau seeds—propagation and convergence in endolysosomal permeabilization

“…What are the fundamental avenues by which tau seeds can propagate from one neuron to another? Propagation can be via extracellular vesicles such as exosomes [10,11,27] or microvesicles [28,29], tunneling nanotubes that establish a direct connection between the cytoplasm of neighboring cells [30,31], transfer of extracellular tau due to mere proximity of cells [15,32,33], or transsynaptic transfer of tau seeds between interconnected neurons [8,10,12,27]. Interestingly, only exosomes [10,27] (Fig 2A ) and vesicle-free tau seeds [8,12] have been shown to propagate transsynaptically (Fig 2B-D), and although tau has been found associated with microvesicles [28,29], to our knowledge there is no study showing that microvesicles can move transsynaptically between interconnected neurons or seed tau aggregation in recipient cells.…”