A Combined Cell-Worm Approach to Search for Compounds Counteracting the Toxicity of Tau Oligomers In Vivo

Abstract

A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo, we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were employed to produce different tau assemblies whose proteotoxic potential was evaluated using C. elegans. Lysates from cells induced for five days significantly reduced the worm’s locomotor activity. This toxic effect was not related to the total amount of tau produced by cells or to its phosphorylation state but was related to the formation of multimeric tau assemblies, particularly tetrameric ones. We investigated the applicability of this approach for testing compounds acting against oligomeric tau toxicity, using doxycycline (Doxy) as a prototype drug. Doxy affected tau solubility and promoted the disassembly of already formed toxic aggregates in lysates of cells induced for five days. These effects translated into a dose-dependent protective action in C. elegans. These findings confirm the validity of the combined HEK T-Rex cells and the C. elegans-based approach as a platform for pharmacological screening.

Aβ1-6A2V(D) peptide, effective on Aβ aggregation, inhibits tau misfolding and protects the brain after traumatic brain injury

“…In this study, we first showed the multitarget potential of Aβ1-6 A2V (D) by confirming that the peptide inhibited the in vitro aggregation of tau even in its mutated P301L form, known to be more prone to misfold. Next, employing C. elegans as a biosensor, we investigated the effect of Aβ1-6 A2V (D) on the proteotoxicity of tau isoforms [ 26 , 27 ]. This approach produced remarkable synergies, enabling us to have a deeper insight into the activity of the Aβ1-6 A2V (D).…”

“…To test our working hypothesis, in this study, we first evaluated the ability of the hexapeptide on the aggregation and stability of recombinant tau. To investigate the effect of Aβ1-6 A2V (D) on tau toxicity, we utilized Caenorhabditis elegans as a biosensor [ 25 – 27 ]. This nematode is capable of specifically detecting toxic tau assemblies, particularly oligomeric assemblies, even when administered exogenously, resulting in neuromuscular impairment.…”

“…This nematode is capable of specifically detecting toxic tau assemblies, particularly oligomeric assemblies, even when administered exogenously, resulting in neuromuscular impairment. By administering brain homogenates from P301L transgenic mice, a well-characterized animal model of tauopathy, to C. elegans , we demonstrated a neuronal defect to that observed with oligomeric recombinant tau [ 27 ]. This well-validated approach provides a useful tool for screening potential pharmacological agents [ 27 ].…”

“…By administering brain homogenates from P301L transgenic mice, a well-characterized animal model of tauopathy, to C. elegans , we demonstrated a neuronal defect to that observed with oligomeric recombinant tau [ 27 ]. This well-validated approach provides a useful tool for screening potential pharmacological agents [ 27 ]. To test the relevance of Aβ1-6 A2V (D) treatment to AD and other dementias involving tau pathology, we used our established traumatic brain injury (TBI) preclinical model [ 28 , 29 ].…”