Targeted autophagic clearance of Tau protects against Alzheimer's disease through amelioration of Tau-mediated lysosomal stress
Bo Hyun Yoon, Jinho Kim, Sandip Sengupta, Chan-Jung Park, Minjoo Ko, Ji Hee Kang, Young Tag Ko, Yeji Kim, S M Lim, Yoonhee Bae, M. Y. Choi, Yunyeong Jang, Ho Jeong Kwon, Hyo Jin Son, Hee Jin Kim, Taebo Sim, Keun‐A Chang, Myung Sik Lee
Abstract
Background: Lysosomal dysfunction could be an underlying cause of Alzheimer's disease, with Tau oligomer being an important inducer or amplifier of lysosomal stress associated with the disease.Tau oligomer is a well-known substrate of autophagy, and selective degradation of Tau with Tau-specific autophagy degrader might be feasible.Methods: Tau-specific autophagic degraders were synthesized by combining leucomethylene blue, linkers and a lysosomal degradation tag (Autac).Tau clearance and changes of Tau-mediated lysosomal stress by these degraders were studied in vitro.In vivo effects of a Tau-specific degrader were investigated employing a combined Tau/A mutant mouse model characterized by an accelerated onset of neurological deficits.Human relevance was investigated using induced pluripotent stem cell (iPSC)-derived neuronal cells from an Alzheimer's disease patient.Results: Among Tau-specific Autac degraders, TauAutac-3 (TA-3) efficiently degraded Tau oligomer and monomer, an effect inhibited by bafilomycin A1, suggesting lysosomal Tau degradation.TA-3 treatment induced LC3, K63, OPTN or NDP52 puncta, which was partially colocalized with Tau oligomer.Signs of lysosomal stress, such as galectin-3 puncta, pHluorin fluorescence, altered lysosomal pH and CHMP2B recruitment, induced by Tau expression were reversed by TA-3.Autophagy impairment by Tau expression in vitro, likely due to lysosomal stress, was also reversed by TA-3.In vivo, TA-3 administration markedly reduced the accumulation of both Tau and A in 6xTg mice, which was associated with amelioration of Tau-mediated lysosomal stress and autophagy impairment.Neuroinflammation characterized by increased numbers of GFAP + glial cells and Iba1 + microglial cells, was also reduced following TA-3 administration.TA-3 remarkably improved neurologic deficits in 6xTg mice, such as impaired memory and reduced exploratory behavior.TA-3 reduced Tau and phospho-Tau accumulation in iPSC-derived neuronal cells from an Alzheimer's disease patient. Conclusion:These results suggest that Tau-specific autophagic (Autac) degraders could serve as novel therapeutic agents for Alzheimer's disease through reduction of Tau-mediated lysosomal stress.