Deficiency of MTH1 and/or OGG1 increases the accumulation of 8-oxoguanine in the brain of the AppNL-G-F/NL-G-F knock-in mouse model of Alzheimer's disease, accompanied by accelerated microgliosis and reduced anxiety-like behavior

Yuri Mizuno, Nona Abolhassani, Guianfranco Mazzei, Takashi Saito, Takaomi C. Saido, Ryo Yamasaki, Jun ichi Kira, Yusaku Nakabeppu

Research output: Contribution to journalArticlepeer-review

Abstract

Oxidative stress is a major risk factor for Alzheimer's disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. 8-oxo-2′-deoxyguanosine triphosphatase (MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MTH1 and/or OGG1 may suppress the pathogenesis of AD; however, their exact roles remain unclear. We evaluated the roles of MTH1 and OGG1 during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice (a preclinical AD model). Six-month-old female AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged; the alteration was less evident in 12-month-old mice. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex of six-month-old mice; the alteration was less evident in 12-month-old mice. Astrocytes and neurons were not influenced. We showed that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, and the effects are age-dependent. MTH1 and/or OGG1 deficiency reduced anxiety-related behavior in AppNL-G-F/NL-G-F mice with a significant acceleration of the 8-oxoG burden and microgliosis, especially in the cortex and amygdala.

Original languageEnglish
JournalNeuroscience Research
DOIs
Publication statusAccepted/In press - 2021

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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