A Tauopathy-Homing and Autophagy-Activating Nanoassembly for Specific Clearance of Pathogenic Tau in Alzheimer’s Disease

Abstract

The hyperphosphorylated and aggregated tau accumulation represents a significant pathological hallmark of tauopathies including Alzheimer’s disease (AD), which is highly associated with defective autophagy in neuronal cells. Autophagy-activating strategies demonstrate the therapeutic potential for AD in many studies; however, further development is limited by their low efficacy and serious side effects that result from a lack of selectivity for diseased cells. Herein, we report a tauopathy-homing nanoassembly (THN) with autophagy-activating capacity for AD treatment. Specifically, the THN can bind to hyperphosphorylated and/or aggregated tau and selectively accumulate in cells undergoing tauopathy. The THN further promotes the clearance of pathogenic tau accumulation by stimulating autophagic flux, consequently rescuing neuron viability and cognitive functions in AD rats. This study presents a promising nanotechnology-based strategy for tauopathy-homing and autophagy-mediated specific removal of pathogenic tau in AD.

The pleiotropic roles of autophagy in Alzheimer's disease: From pathophysiology to therapy

“…Likewise, a tauopathy-homing nanoassembly containing PEGylated ceria nanoparticles modulates the mTOR–TFEB axis through AKT signalling. Treatment with this nanomaterial elicits autophagy-dependent tau proteolysis and ameliorates cognitive dysfunction in an AD rat model [ 37 ]. Finally, inhibition of p300-mediated acetylation by SMDC37892 also leads to a beneficial effect on tau turnover in human iPSC-derived excitatory neurons potentially due to mTORC1 inhibition caused by decreased raptor acetylation [ 20 , 21 ].…”

Protein-Mimicking Nanoparticles for a Cellular Regulation of Homeostasis

“…Sun et al fabricated nanoceria in a tauopathy-homing nanoassembly (THN) that binds to hyperphosphorylated and/or aggregated tau. The THN promoted lysosomal degradation of pathogenic tau via inducing autophagic flux and rescued neuron viability and cognitive functions in AD rats . In addition, NPs can also regulate the protein turnover in an autophagy-independent manner.…”

“…The THN promoted lysosomal degradation of pathogenic tau via inducing autophagic flux and rescued neuron viability and cognitive functions in AD rats. 19 In addition, NPs can also regulate the protein turnover in an autophagy-independent manner. Zhang et al demonstrated that MnFe 2 O 4 NPs accelerated the clearance of mutant huntingtin protein aggregates through the ubiquitin-proteasome system instead of the autophagy-lysosome pathway.…”

Tau-targeting therapy in Alzheimer’s disease: critical advances and future opportunities

“…miR-132/212 levels are correlated with insoluble tau and cognitive impairment in humans [155] . Blocking cholesterol acyltransferase expression with inhibitors revealed enhanced autophagy and induced autophagosome formation in AD mouse models, accompanied by a decrease in phosphorylated tau [156] .…”