After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggre...After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.展开更多
基金financially supported by the National Natural Science Foundation of China (Nos. 51933006 and 52073306)Young Elite Scientists Sponsorship Program by Tianjin (No. TJSQNTJ-2020-18)+1 种基金the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (No. 2019-RC-HL-014)Wenzhou Key Laboratory of Biomaterials and Engineering (No. WIUCASSWCL21004)
文摘After repeated frustrations with amyloid beta(Aβ)-targeted clinical trials for Alzheimer’s disease(AD)in recent years,the therapeutic focus of AD has gradually shifted from Aβto tau protein.The misfolding and aggregation of tau protein into neurofibrillary tangles(NFTs)cause neuron death and synaptic dysfunction,and the deposition of NFTs is more closely related to the severity of AD than Aβplaques.Thus,it has great potential to target tau protein aggregation for AD treatment.The hexapeptide VQIVYK(known as PHF6)in tau protein has been found to play a dominant role for tau aggregation and was widely used as a model to design tau protein aggregation inhibitors.Here,inspired by natural heat shock protein(HSPs),we fabricated a self-assembly nanochaperone based on mixed-shell polymeric micelle(MSPM)as a novel tau-targeted AD therapy.With tunable phase-separated microdomains on the surface,the nanochaperone could effectively bind with PHF6 aggregates,inhibit PHF6 aggregation,block neuronal internalization of PHF6 species,thus significantly alleviating PHF6 mediated neurotoxicity.Moreover,the as-prepared nanochaperone could work with proteinase to facilitate the degradation of PHF6 aggregates.This bioinspired nanochaperone demonstrated a new way to target tau protein and provided a promising strategy for AD treatment.
