title: Derlin-1-immunopositive inclusions in patients with Alzheimer's disease.
abstract: Amyloid plaques and neurofibrillary tangles are the major pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles are composed of filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Derlin proteins are a family of proteins that are conserved in all eukaryotes, in which they function in endoplasmic reticulum-associated degradation. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins in the luminal space of the endoplasmic reticulum. In this study, we found that derlin-1 and PDI were colocalized in neurofibrillary tangles in the brain of patients with Alzheimer's disease. Derlin-1 and PDI may work as partners to avoid the accumulation of unfolded proteins in Alzheimer's disease. Furthermore, we found that derlin-1 was immunopositive for neurofibrillary tangles and upregulated in Alzheimer's disease and that derlin-1 may play an important role in endoplasmic reticulum-associated degradation during the pathogenesis of Alzheimer's disease. We hypothesize that derlin-1 was upregulated to avoid the aggregation of unfolded proteins. Despite the upregulation of derlin-1, the functions of chaperone proteins and Alzheimer tau protein were lost and these proteins were also accumulated. Finally, they were involved in neurofibrillary tangles. These results suggest that derlin-1 may be associated with endoplasmic reticulum stress in neuronal cells in Alzheimer's disease.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Sakyoku, Koyoto, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Honjo
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Aki
authors.initials: A
authors.lastname: Nakanishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism*; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C487709:DERL1 protein, human; D008565:Membrane Proteins