title: Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer's disease.
abstract: Neurofibrillary tangles (NFTs), composed of truncated and hyperphosphorylated tau, are a common feature of numerous aging-related neurodegenerative diseases, including Alzheimer's disease (AD). However, the molecular mechanisms mediating tau truncation and aggregation during aging remain elusive. Here we show that asparagine endopeptidase (AEP), a lysosomal cysteine proteinase, is activated during aging and proteolytically degrades tau, abolishes its microtubule assembly function, induces tau aggregation and triggers neurodegeneration. AEP is upregulated and active during aging and is activated in human AD brain and tau P301S-transgenic mice with synaptic pathology and behavioral impairments, leading to tau truncation in NFTs. Tau P301S-transgenic mice with deletion of the gene encoding AEP show substantially reduced tau hyperphosphorylation, less synapse loss and rescue of impaired hippocampal synaptic function and cognitive deficits. Mice infected with adeno-associated virus encoding an uncleavable tau mutant showed attenuated pathological and behavioral defects compared to mice injected with adeno-associated virus encoding tau P301S. Together, these observations indicate that AEP acts as a crucial mediator of tau-related clinical and neuropathological changes. Inhibition of AEP may be therapeutically useful for treating tau-mediated neurodegenerative diseases.
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA. [2] Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Mingke
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Seong Su
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Il-Sun
authors.initials: IS
authors.lastname: Kwon
authors.affiliation: 1] Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA. [2] Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.affiliation: 1] Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA. [2] Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: William T
authors.initials: WT
authors.lastname: Hu
authors.affiliation: Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhixue
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China.
authors.forename: Liming
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.affiliation: 1] Center for Neurodegenerative Diseases, Emory University School of Medicine, Atlanta, Georgia, USA. [2] Department of Neurology, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
mesh_terms: D000368:Aged; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology* / Q000473:pathology* / Q000503:physiopathology; D000595:Amino Acid Sequence; D000818:Animals; D001216:Asparagine / Q000378:metabolism; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002154:Calpain / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D003071:Cognition; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D008569:Memory Disorders / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000201:enzymology* / Q000473:pathology*; D009498:Neurotoxins / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012995:Solubility; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*; D000099240:Asparaginyl Endopeptidase
chemical_list: D001216:Asparagine; D002154:Calpain; D020169:Caspases; D003546:Cysteine Endopeptidases; D009498:Neurotoxins; D016875:tau Proteins; D000099240:Asparaginyl Endopeptidase