Inhibitory RNA Aptamers of Tau Oligomerization and Their Neuroprotective Roles against Proteotoxic Stress.
Tau is a cytosolic protein that functions in the assembly and stabilization of axonal microtubule networks. Its oligomerization may be the rate-limiting step of insoluble aggregate formation, which is a neuropathological hallmark of Alzheimer's disease (AD) and a number of other tauopathies. Recent evidence indicates that soluble tau oligomers are the toxic species for tau-mediated pathology during AD progression. Herein, we describe novel RNA aptamers that target human tau and were identified through an in vitro selection process. These aptamers significantly inhibited the oligomerization propensity of tau both in vitro and in cultured cell models of tauopathy without affecting the half-life of tau. Tauopathy model cells treated with the aptamers were less sensitized to proteotoxic stress induced by tau overexpression. Moreover, the tau aptamers significantly alleviated synthetic tau oligomer-mediated neurotoxicity and dendritic spine loss in primary hippocampal neurons. Thus, our study demonstrates that delaying tau assembly with RNA aptamers is an effective strategy for protecting cells under various neurodegenerative stresses originating from pathogenic tau oligomerization.
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.|Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.
Ji Hyeon
JH
Kim
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.
Eunkyoung
E
Kim
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.|Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.
Won Hoon
WH
Choi
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.|Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.
Jeeyoung
J
Lee
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.
Jung Hoon
JH
Lee
Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.|Neuroscience Research Institute, Seoul National University College of Medicine , Seoul 03080, Korea.
Hyojin
H
Lee
Department of Bioscience and Biotechnology, Konkuk University , Seoul 05029, Korea.
Dong-Eun
DE
Kim
Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.|Neuroscience Research Institute, Seoul National University College of Medicine , Seoul 03080, Korea.
Young Ho
YH
Suh
Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul 03080, Korea.|Department of Biomedical Sciences, Seoul National University Graduate School , Seoul 03080, Korea.|Biomedical Research Institutue, Seoul National University Hospital , Seoul 03080, Korea.
Min Jae
MJ
Lee
D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D052157:Aptamers, Nucleotide / Q000037:antagonists & inhibitors*; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058105:Polymerization / Q000187:drug effects*; D012313:RNA / Q000037:antagonists & inhibitors*; D051381:Rats; D013312:Stress, Physiological / Q000187:drug effects*; D024801:Tauopathies / Q000188:drug therapy; D016875:tau Proteins / Q000037:antagonists & inhibitors*
D052157:Aptamers, Nucleotide; D018696:Neuroprotective Agents; D016875:tau Proteins; D012313:RNA
Alzheimer’s disease; SELEX; aggregation; aptamer; inhibition; neurotoxicity; oligomerization; tau; tauopathy