Nitrative Stress and Tau Accumulation in Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (ALS/PDC) in the Kii Peninsula, Japan.

Yukiko Hata,Satoru Morimoto,Yasumasa Kokubo,Shosuke Kawanishi,Ning Ma,Misao Yoneda,Hideyuki Okano,Shigeo Murayama,Shigeki Kuzuhara

doi:10.3389/fnins.2017.00751

Abstract

Objective: The Kii Peninsula of Japan is known to be a high incidence area of amyotrophic lateral sclerosis/parkinsonism-dementia complex (Kii ALS/PDC) with tauopathy. Nitrative stress and oxidative stress on ALS/PDC and their relationship to tau pathology were clarified.Methods: Seven patients with Kii ALS/PDC (3 males and 4 females, average age 70.7 years, 3 with ALS, 2 with ALS with dementia, and 2 with PDC) were analyzed in this study. Five patients with Alzheimer's disease and five normal aged subjects were used as controls. Immunohistochemical analysis was performed on formalin-fixed, paraffin-embedded temporal lobe sections (the hippocampal area including hippocampus, prosubiculum, subiculum, presubiculum, and parahippocampal gyri) using antibodies to detect phosphorylated tau (anti-AT-8), nitrated guanine (anti-8-NG), anti-iNOS, anti-NFκB, and oxidized guanine (anti-8-OHdG) antibodies.Results: Most hippocampal neurons of Kii ALS/PDC patients were stained with anti-8-NG, anti-iNOS, anti-NFκB, and anti-8-OHdG antibodies and some AT-8 positive neurons were co-stained with anti-8-NG antibody. The numbers of 8-NG positive neurons and 8-OHdG positive neurons were greater than AT-8 positive neurons and the number of 8-NG positive neurons was larger in patients with Kii ALS/PDC than in controls.Conclusion: Nitrative and oxidative stress may take priority over tau accumulation and lead to the neurodegeneration in Kii ALS/PDC.

Highlights

The Kii Peninsula is the high-incidence focus of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in Japan (Kokubo and Kuzuhara, 2001)
Most hippocampal neurons of Kii ALS/PDC patients were stained with anti-8-NG, anti-inducible nitric oxide synthase (iNOS), anti-NFκB, and anti-8-OHdG antibodies and some AT-8 positive neurons were co-stained with anti-8-NG antibody
The numbers of 8-NG positive neurons and 8-OHdG positive neurons were greater than AT-8 positive neurons and the number of 8-NG positive neurons was larger in patients with Kii ALS/PDC than in controls

Summary

Introduction

The Kii Peninsula is the high-incidence focus of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) in Japan (Kokubo and Kuzuhara, 2001). We investigated the interaction between OS, NS, and tau in the pathogenesis of Kii ALS/PDC using immunohistological analyses with the following five antibodies: anti-8-nitroguanine (8-NG), which detects nitrated guanine in DNA and RNA (Ma et al, 2004, 2006; Pinlaor et al, 2004a,b), anti-8-OHdG, which detects oxidized guanine in RNA (Kikuchi et al, 2002; Nunomura et al, 2004), anti-inducible nitric oxide synthase (iNOS) (Levecque et al, 2003; Fernández-Vizarra et al, 2004; Ma et al, 2004, 2006; Pinlaor et al, 2004a,b), anti-NFκB which induces iNOS, and anti-AT-8 antibody, which detects phosphorylated tau (p-tau). We found that OS and especially NS, were concerned with tau deposition in the Kii ALS/PDC patients’ brains

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Discussion

Conclusion