Harnessing Nanochaperone‐Mediated Autophagy for Selective Clearance of Pathogenic Tau Protein in Alzheimer's Disease

Accumulation of pathological tau is a hallmark of Alzheimer's disease (AD), which correlates more closely with cognitive impairment than does the amyloid‐β (Aβ) burden. Autophagy is a powerful process for the clearance of toxic proteins including aberrant tau. However, compromised autophagy is demonstrated in neurodegeneration including AD, and current autophagy inducers remain enormously challenging due to inability of restoring autophagy pathway and lack of targeting specificity. Here, pathogenic tau‐specific autophagy based on customized nanochaperone is developed for AD treatment. In this strategy, the nanochaperone can selectively bind to pathogenic tau and maintain tau homeostasis, thereby ensuring microtubule stability which is important for autophagy pathway. Meanwhile, the bound pathogenic tau can be sequestered in autophagosomes by in situ autophagy activation of nanochaperone. Consequently, autophagosomes wrapping with pathogenic tau are able to be trafficked along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in the enhancement of autophagic flux and pathologic tau clearance. After treatment with this nanochaperone‐mediated autophagy strategy, the tau burden, neuron damages, and cognitive deficits of AD mice are significantly alleviated in the brain. Therefore, this work represents a promising candidate for AD‐targeted therapy and provides new insights into future design of anti‐neurodegeneration drugs. This research demonstrates a nanochaperone‐mediated‐autophagy‐based strategy that can specifically recognize pathogenic tau and recruit them, thereby maintaining the tau homeostasis to guarantee microtubule stability. Meanwhile, the captured pathogenic tau can be sequestered by in situ autophagy activation and transported along the stabilized microtubule to achieve successful fusion with lysosomes, resulting in selective clearance of pathogenic tau protein in Alzheimer's disease.