Protein Disulfide Isomerase P5-Immunopositive Inclusions in Patients with Alzheimer's Disease

Article type: Research Article

Authors: Honjo, Yasuyuki^{a; b; 1} | Horibe, Tomohisa^{a; 1} | Torisawa, Aya^a | Ito, Hidefumi^c | Nakanishi, Aki^d | Mori, Hiroshi^e | Komiya, Tohru^f | Takahashi, Ryosuke^b | Kawakami, Koji^{a; *}

Affiliations: [a] Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan | [b] Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan | [c] Department of Neurology, Graduate School of Medicine, Wakayama Medical University, Wakayama, Japan | [d] Department of Neurology and Psychiatry, Osaka City Kosaiin Hospital, Osaka, Japan | [e] Department of Neurology and Neuroscience, Osaka City University Medical School, Osaka, Japan | [f] Faculty of Bioscience, Nagahama Institute of Bioscience and Technology, Shiga, Japan

Correspondence: [*] Correspondence to: Koji Kawakami, Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto 606-8501, Japan. Tel.: +81 75 753 4459; Fax: +81 75 753 4469; E-mail: kawakami.koji.4e@kyoto-u.ac.jp.

Note: [1] These authors contributed equally to this work.

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.

Keywords: Alzheimer's disease, endoplasmic reticulum stress, misfolding, neurofibrillary tangle, nitric oxide, protein disulfide isomerase, protein disulfide isomerase P5, S-nitrosylation, tau

DOI: 10.3233/JAD-130632

Journal: Journal of Alzheimer's Disease, vol. 38, no. 3, pp. 601-609, 2014