<学術雑誌論文>
MTH1 and OGG1 maintain a low level of 8‑oxoguanine in Alzheimer’s brain, and prevent the progression of Alzheimer’s pathogenesis

作成者
本文言語
出版者
発行日
収録物名
出版タイプ
アクセス権
権利関係
権利関係
関連DOI
関連DOI
関連URI
関連HDL
概要 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.続きを見る

本文ファイル

pdf 4482066 pdf 11.8 MB 347  

詳細

EISSN
レコードID
査読有無
関連PubMed ID
タイプ
助成情報
登録日 2021.07.14
更新日 2024.12.02

この資料を見た人はこんな資料も見ています