title: Tissue Transglutaminase and Its Product Isopeptide Are Increased in Alzheimer's Disease and APPswe/PS1dE9 Double Transgenic Mice Brains.
abstract: Alzheimer's disease (AD) is characterized by intracellular and extracellular protein aggregates, including microtubule-associated protein tau and cleavage product of amyloid precursor protein, β-amyloid (Aβ). Tissue transglutaminase (tTG) is a calcium-dependent enzyme that cross-links proteins forming a γ-glutamyl-ε-lysine isopeptide bond. Highly resistant to proteolysis, this bond can induce protein aggregation and deposition. We set out to determine if tTG may play a role in pathogenesis of AD. Previous studies have shown that tTG and isopeptide are increased in advanced AD, but they have not addressed if this is an early or late feature of AD. In the present study, we measured tTG expression levels and enzyme activity in the brains of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD, as well as a transgenic mouse model of AD. We found that both enzyme expression and activity were increased in MCI as well as AD compared to NCI. In the transgenic model of AD, tTG expression and enzyme activity increased sharply with age and were relatively specific for the hippocampus. We also assessed overlap of isopeptide immunoreactivity with neurodegeneration-related proteins with Western blots and found neurofilament, tau, and Aβ showed co-localization with isopeptide in both AD and transgenic mice. These results suggest that tTG might be a key factor in pathogenesis of abnormal protein aggregation in AD.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China.
authors.forename: Ji
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Nutrition and Food Health, School of Public Health, Wuhan University, Wuhan, China.
authors.forename: Suqing
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, 1300 University Avenue, Madison, WI, 53706, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: Department of Pathology (Neuropathology) and Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, 32224, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin, 1300 University Avenue, Madison, WI, 53706, USA. dwang6@wisc.edu.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai, 200237, China. ruiwang@ecust.edu.cn.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000150:complications / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D060825:Cognitive Dysfunction / Q000150:complications / Q000473:pathology; D003432:Cross-Linking Reagents / Q000378:metabolism; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology; D010455:Peptides / Q000378:metabolism*; D053764:Presenilin-1 / Q000378:metabolism*; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D010455:Peptides; D053764:Presenilin-1; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Aggregate; Alzheimer’s disease (AD); Cross-link; Isopeptide; Tissue transglutaminase (tTG); γ-Glutamyl-ε-lysine