title: Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases.
abstract: Oxidative stress has been proposed as a potential mechanism for neurodegenerative diseases, such as Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). In response to oxidative stress, the levels of numerous cytoprotective products are increased via alteration of the Kelch-like ECH-associated protein 1 (Keap1) and NF-E2-related factor 2 (Nrf2) system. One of the Nrf2 targets, p62, has been known to be incorporated into a wide spectrum of cytoplasmic inclusions in neurodegenerative diseases and interact with Keap1. However, it remains unclear whether Keap1 is associated with the pathogenesis of neurodegenerative diseases. In this study, we investigated the relationship between p62 and Keap1 in the brains of patients with AD, PD, dementia with Lewy bodies (DLB), and ALS. Biochemical analyses showed that p62 and Keap1 interacted with each other in AD and DLB brains and were extracted into similar detergent-soluble and -insoluble fractions. Pathologic examination demonstrated that anti-Keap1 antibodies immunostained Lewy bodies in PD and DLB, neurofibrillary tangles in AD, and skeinlike inclusions in ALS. Further analysis showed that the levels of common Nrf2 target genes were increased in AD compared with those in controls. However, there were no statistical significances in the levels of Nrf2 target genes in DLB relative to controls. Our pathologic and biochemical results suggest a molecular basis for stress response to be involved in the formation of cytoplasmic inclusions observed in several neurodegenerative diseases.
authors.affiliation: Department of Neuropathology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan. kunikazu@cc.hirosaki-u.ac.jp
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tanji
authors.forename: Atsushi
authors.initials: A
authors.lastname: Maruyama
authors.forename: Saori
authors.initials: S
authors.lastname: Odagiri
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001923:Brain Chemistry / Q000502:physiology; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1