MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis

Abstract 8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer’s disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired wit...

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Autores principales:	Sugako Oka, Julio Leon, Kunihiko Sakumi, Nona Abolhassani, Zijing Sheng, Daisuke Tsuchimoto, Frank M. LaFerla, Yusaku Nakabeppu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2da47d76ddfd4f32a7a7bc3c676d5685
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spelling	oai:doaj.org-article:2da47d76ddfd4f32a7a7bc3c676d56852021-12-02T16:36:12ZMTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis10.1038/s41598-021-84640-92045-2322https://doaj.org/article/2da47d76ddfd4f32a7a7bc3c676d56852021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84640-9https://doaj.org/toc/2045-2322Abstract 8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer’s disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.Sugako OkaJulio LeonKunihiko SakumiNona AbolhassaniZijing ShengDaisuke TsuchimotoFrank M. LaFerlaYusaku NakabeppuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sugako Oka Julio Leon Kunihiko Sakumi Nona Abolhassani Zijing Sheng Daisuke Tsuchimoto Frank M. LaFerla Yusaku Nakabeppu MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
description	Abstract 8-Oxoguanine (8-oxoG), a major oxidative base lesion, is highly accumulated in Alzheimer’s disease (AD) brains during the pathogenic process. MTH1 hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP, thereby avoiding 8-oxo-dG incorporation into DNA. 8-OxoG DNA glycosylase-1 (OGG1) excises 8-oxoG paired with cytosine in DNA, thereby minimizing 8-oxoG accumulation in DNA. Levels of MTH1 and OGG1 are significantly reduced in the brains of sporadic AD cases. To understand how 8-oxoG accumulation in the genome is involved in AD pathogenesis, we established an AD mouse model with knockout of Mth1 and Ogg1 genes in a 3xTg-AD background. MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and, to a lesser extent, mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age. Furthermore, minocycline, which inhibits microglial activation and reduces neuroinflammation, markedly decreased the nuclear accumulation of 8-oxoG in microglia, and inhibited microgliosis and neuronal loss. Gene expression profiling revealed that MTH1 and OGG1 efficiently suppress progression of AD by inducing various protective genes against AD pathogenesis initiated by Aß/Tau accumulation in 3xTg-AD brain. Our findings indicate that efficient suppression of 8-oxoG accumulation in brain genomes is a new approach for prevention and treatment of AD.
format	article
author	Sugako Oka Julio Leon Kunihiko Sakumi Nona Abolhassani Zijing Sheng Daisuke Tsuchimoto Frank M. LaFerla Yusaku Nakabeppu
author_facet	Sugako Oka Julio Leon Kunihiko Sakumi Nona Abolhassani Zijing Sheng Daisuke Tsuchimoto Frank M. LaFerla Yusaku Nakabeppu
author_sort	Sugako Oka
title	MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
title_short	MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
title_full	MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
title_fullStr	MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
title_full_unstemmed	MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis
title_sort	mth1 and ogg1 maintain a low level of 8-oxoguanine in alzheimer's brain, and prevent the progression of alzheimer's pathogenesis
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/2da47d76ddfd4f32a7a7bc3c676d5685
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MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer's brain, and prevent the progression of Alzheimer's pathogenesis

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