Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons

Abstract

Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies.

Glutamatergic dysfunction precedes neuron loss in cerebral organoids withMAPTmutation

“…No genotypedependent differences were observed at 2 months of differentiation. The increased burden of tau with age mirrors prior observations in 2D iPSC-derived neuronal models (Ehrlich et al, 2015;Fong et al, 2013;Iovino et al, 2015;Silva et al, 2016Silva et al, , 2020Wren et al, 2015) and in human brain from V337M carriers (Spillantini et al, 1996;Spina et al, 2017).…”

Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol

“…We speculate that the initiation of seeded tau aggregation may be restricted to a time window before autophagosomes form and surround exosome-containing endolysosomes, given that this double containment could interfere with the continuous escape of tau seeds and the ensuing aggregation process. Therefore, pharmacological stimulation of autophagy might not only contribute to the clearance of pre-existing tau pathology as previously shown [ 63 , 64 ], but also may interfere with the generation of de novo tau aggregates triggered by exosomal tau seeds.…”

Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

“…In other words, deficient autophagy can be causal to disease, or its failure can be secondary to alterations in other quality control mechanisms. Nonetheless, this pathway seems to be amenable to genetic and pharmacological enhancement, which can reduce tau levels and aggregation, mitigating spreading and neuronal loss [ 193 , 201 , 202 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 ]. Based on these observations, enhancement of autophagy-lysosomal function can have critically relevant therapeutic implications [ 159 , 195 , 202 , 212 , 213 , 214 , 215 , 216 , 217 ].…”

“…The autophagy-lysosomal pathway is recognized as the main mechanism for clearance of protein aggregates that cannot be proteolyzed by the proteasome. Whether autophagy and lysosomal impairment are contributors or a consequence of tauopathy is unclear [ 154 , 159 ], but many studies have shown evidence that pharmacological enhancement of autophagy activity in patient-derived neurons and in vivo can reduce oligomeric and aggregated tau, mitigate tau neuronal transmission, and reduce cell loss, supporting a role for autophagy modulators in therapeutics [ 159 , 193 , 206 , 207 , 208 , 211 , 212 , 213 , 215 , 216 , 217 ]. Several activators of autophagy have been put forward [ 159 , 212 , 214 , 215 ], but none have yet shown efficacy in the human brain at patient-tolerated doses, or successful outcome in clinical trials.…”