8-oxoguanine causes spontaneous de novo germline mutations in mice.

Spontaneous germline mutations generate genetic diversity in populations of sexually reproductive organisms, and are thus regarded as a driving force of evolution. However, the cause and mechanism remain unclear. 8-oxoguanine (8-oxoG) is a candidate molecule that causes germline mutations, because it makes DNA more prone to mutation and is constantly generated by reactive oxygen species in vivo. We show here that endogenous 8-oxoG caused de novo spontaneous and heritable G to T mutations in mice, which occurred at different stages in the germ cell lineage and were distributed throughout the chromosomes. Using exome analyses covering 40.9 Mb of mouse transcribed regions, we found increased frequencies of G to T mutations at a rate of 2 × 10(-7) mutations/base/generation in offspring of Mth1/Ogg1/Mutyh triple knockout (TOY-KO) mice, which accumulate 8-oxoG in the nuclear DNA of gonadal cells. The roles of MTH1, OGG1, and MUTYH are specific for the prevention of 8-oxoG-induced mutation, and 99% of the mutations observed in TOY-KO mice were G to T transversions caused by 8-oxoG; therefore, we concluded that 8-oxoG is a causative molecule for spontaneous and inheritable mutations of the germ lineage cells

Altered Expression of Diabetes-Related Genes in Alzheimer's Disease Brains: The Hisayama Study

Diabetes mellitus (DM) is considered to be a risk factor for dementia including Alzheimer's disease (AD). However, the molecular mechanism underlying this risk is not well understood. We examined gene expression profiles in postmortem human brains donated for the Hisayama study. Three-way analysis of variance of microarray data from frontal cortex, temporal cortex, and hippocampus was performed with the presence/absence of AD and vascular dementia, and sex, as factors. Comparative analyses of expression changes in the brains of AD patients and a mouse model of AD were also performed. Relevant changes in gene expression identified by microarray analysis were validated by quantitative real-time reverse-transcription polymerase chain reaction and western blotting. The hippocampi of AD brains showed the most significant alteration in gene expression profile. Genes involved in noninsulin-dependent DM and obesity were significantly altered in both AD brains and the AD mouse model, as were genes related to psychiatric disorders and AD. The alterations in the expression profiles of DM-related genes in AD brains were independent of peripheral DM-related abnormalities. These results indicate that altered expression of genes related to DM in AD brains is a result of AD pathology, which may thereby be exacerbated by peripheral insulin resistance or DM

Comparative profiling of cortical gene expression in Alzheimers disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation.

Alzheimers disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aβ pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App NL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in App NL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App NL-G-F/NL-G-F cortex as Aβ amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App NL-G-F/NL-G-F cortex also had altered expression of genes (Abi3, Apoe, Bin2, Cd33, Ctsc, Dock2, Fcer1g, Frmd6, Hck, Inpp5D, Ly86, Plcg2, Trem2, Tyrobp) defined as risk factors for AD by genome-wide association study or identified as genetic nodes in late-onset AD. These results suggest a strong correlation between cortical Aβ amyloidosis and the neuroinflammatory response and provide a better understanding of the involvement of gender effects in the development of AD

Author Correction: Comparative profiling of cortical gene expression in Alzheimer’s disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation

This article contains errors in the Introduction, where “AppNL-G-F/NL-G-F mice carrying the homozygous mutant App gene encoding the humanised Aβ sequence (G601R, F606Y, and R609H) with three pathogenic mutations, namely Swedish (KM595/596NL), Beyreuther/Iberian (I641F), and Arctic (E618G)10, progressively exhibit Aβ accumulation starting at 4 to 6 months of age, dense distributions of microglia and astrocytes from 9 months of age, and behavioural symptoms from 8 to 12 months of age10,11.” should read: “AppNL-G-F/NL-G-F mice carrying the homozygous mutant App gene encoding the humanised Aβ sequence (G676R, F681Y, and R684H) with three pathogenic mutations, namely Swedish (KM670/671NL), Beyreuther/Iberian (I716F), and Arctic (E693G)10, progressively exhibit Aβ accumulation starting at 4 to 6 months of age, dense distributions of microglia and astrocytes from 9 months of age, and behavioural symptoms from 8 to 12 months of age10,11.” In addition, in the Methods section, under the subheading ‘Animals’, “Heterozygous App+/NL-G-F mice carrying humanised Aβ sequence (G601R, F606Y, R609H), Swedish (ML595/596NL), Beyreuther/Iberian (I641F), and Arctic (E618G) mutations, were previously established10.” should read: “Heterozygous App+/NL-G-F mice carrying humanised Aβ sequence (G676R, F681Y, R684H), Swedish (KM670/671NL), Beyreuther/Iberian (I716F), and Arctic (E693G) mutations, were previously established10.