Neurons need to survive and function throughout the life of the individual. However, postmitotic neurons are known to be lost owing to dysfunction associated with aging, particularly via oxidative stress. Consequently, several defense mechanisms function to retain neural networks, including the supply of newborn neurons from neural progenitors in the adult brain. Despite the many defense mechanisms evolved by eukaryotic cells, various oxidized lipids, proteins, carbohydrates and nucleic acids have been found to accumulate in the brains of animals including humans during aging, and under pathological conditions.
Among all nucleobases, guanine is the most susceptible to oxidation, and is modified to 8-oxo-7,8-dihydro-guanine (8-oxoG), which is one of the major oxidized bases in the nucleotide pool or DNA, and is known to be highly accumulated in patient’s brains with aging-related neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and Huntington’s disease. In mammals, including humans, MTH1 with 8-oxo-dGTPase and OGG1 with 8-oxoG DNA glycosylase minimize 8-oxoG accumulation in genomic DNA.
In the present study, we investigated age-related alterations in behavior, 8-oxoG levels, and neurogenesis in the brains of Mth1/Ogg1-double knockout (TO-DKO), Ogg1-knockout, and human MTH1-transgenic (hMTH1-Tg) mice. Spontaneous locomotor activity in the home cage was significantly decreased in wild-type mice with age, and females consistently exhibited higher locomotor activity than males. This decrease was significantly suppressed in female but not male TO-DKO mice and markedly enhanced in female hMTH1-Tg mice. Long-term memory retrieval was impaired in middle-aged female TO-DKO mice. 8-OxoG accumulation significantly increased in nuclear DNA, particularly in the dentate gyrus (DG), subventricular zone (SVZ) and major island of Calleja (ICjM) in middle-aged female TO-DKO mice. In middle-aged female TO-DKO mice, neurogenesis was severely impaired in SVZ and DG, accompanied by ICjM and DG atrophy. Conversely, expression of hMTH1 efficiently suppressed 8-oxoG accumulation in both SVZ and DG with hypertrophy of ICjM. These findings indicate that increased accumulation of 8-oxoG in nuclear DNA of neural progenitors in females is caused by 8-oxo-dGTP incorporation into the nuclear genome during proliferation, causing depletion of neural progenitors, altered behavior, and cognitive function changes with age, as sexually dimorphic phenotypes.