Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies

Abstract

BackgroundIn sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer’s disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau.ResultsUsing a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one.ConclusionTaken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.

Astrogliopathy in Tauopathies

“…The exact mechanism of transmission is not known. Release and trans-synaptic transmission of tau [164,165], tau uptake via exosomes [166][167][168] or nanotubules [169] and free uptake of fibrillar proteins [170,171] have all been suggested as putative mechanisms using cultured neurons. Although astrocyte-to-neuron intercellular transfer mediated by cell-to-cell contact has been postulated for prions [172], no information is available concerning astrocyte-to-neuron transfer in tauopathies.…”

Proteopathic tau seeding predicts tauopathy in vivo

“…Tau seeding requires a critical unit of size for activity, as only particular species propagate the aggregated state (16). In vivo studies have described tau protein spreading from local sites to distant regions, presumably via transsynaptic movement (11,12,(17)(18)(19). Finally, our laboratory and another recently demonstrated that tau propagates discrete amyloid conformations through the brains of animals that give rise to unique neuropathologies (18,20).…”

Tau Monoclonal Antibody Generation Based on Humanized Yeast Models

“…Another important aspect is disease propagation by the secretion and uptake of Tau oligomers that act as seeding templates for Tau misfolding and toxicity (63). In this context, we recently developed a lentivirus-mediated rat model that allowed us to monitor the spreading of Tau pathology from the CA1 region of the hippocampus to other brain areas, including the most distant ones (64,65). We then already used ADx215 as marker to demonstrate that the propagating Tau entity was not phosphorylated at Tyr 18 (65).…”

“…In this context, we recently developed a lentivirus-mediated rat model that allowed us to monitor the spreading of Tau pathology from the CA1 region of the hippocampus to other brain areas, including the most distant ones (64,65). We then already used ADx215 as marker to demonstrate that the propagating Tau entity was not phosphorylated at Tyr 18 (65). Because ADx215 does not recognize higher order oligomers, the data suggest that Tau monomers or the 130-kDa low order oligomers are propagating Tau entities.…”