title: Protein disulfide isomerase P5-immunopositive inclusions in patients with Alzheimer's disease.
abstract: Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological characteristics of Alzheimer's disease (AD). NFTs are composed of tubular filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature of AD is excessive generation of nitric oxide (NO). Protein disulfide isomerase (PDI) is a chaperon protein located in the endoplasmic reticulum (ER). It was recently reported that NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. In addition, we previously reported the presence of PDI-immunopositive NFTs in AD. Here, we found that protein disulfide isomerase P5 (P5), which is a member of the PDI protein family, was co-localized with tau in NFTs. To our knowledge, this is the first report of P5-immunopositive inclusion in AD. Furthermore, we showed that S-nitrosylated P5 was present and the expression level of P5 was decreased in AD brains compared with that of control brains. We also demonstrated that the knock-down of PDI or P5 by siRNA could affect the viability of SH-SY5Y cells under ER stress. Previously, the observation of S-nitrosylated PDI in AD was reported. NO may inhibit P5 by inducing S-nitrosylation in the same manner as PDI, which inhibits its enzymatic activity allowing protein misfolding to occur in AD. The accumulation of misfolded proteins induces ER stress and may cause apoptosis of neuronal cells through S-nitrosylation and down-regulation of PDI and P5 in AD.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Honjo
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Aya
authors.initials: A
authors.lastname: Torisawa
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Aki
authors.initials: A
authors.lastname: Nakanishi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mori
authors.forename: Tohru
authors.initials: T
authors.lastname: Komiya
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 / Q000473:pathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009447:Neuroblastoma / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000201:enzymology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016875:tau Proteins; C526506:PDIA5 protein, human; D019704:Protein Disulfide-Isomerases
keywords: Alzheimer's disease; S-nitrosylation; endoplasmic reticulum stress; misfolding; neurofibrillary tangle; nitric oxide; protein disulfide isomerase; protein disulfide isomerase P5; tau