Alzheimer’s gene a double whammy

An international team, including researchers from the University of Melbourne, has found that a gene called ApoE4, which is known to be associated with an increased risk of developing Alzheimer’s, also influences the harmful accumulation of the protein tau in the brains of mice. ApoE4 is known to influence the deposition of amyloid-b, the protein that forms clumps in the brains of patients with Alzheimer’s, but this study, published in Nature, is the first to show that the gene also influences tau pathology, another major signature of the disease. ApoE4 was identified as a strong genetic risk factor for late-onset Alzheimer’s disease in 1993, but the mechanisms that underlie its contribution to the disease remain poorly understood. ApoE4 is known to influence the deposition of amyloid-b protein, a key initiator of Alzheimer’s disease, in the brain. However, it has remained unclear whether the gene variant also influences tau pathology, another major signature of the disease. Using a mouse model of tauopathy (where tau aggregates harmfully in tangles in the brain), the researchers showed that the ApoE4 protein influences tau pathogenesis, and increases neuroinflammation and tau-mediated neurodegeneration independent of amyloid-b pathology in the brain. They found that, in mice, ApoE4 exerts a “toxic” gain of function on these processes, whereas its absence seems to be protective, attenuating tau-mediated neuroinflammation and neurodegeneration. Further work is needed to determine whether the findings can be translated to the clinic, but the study suggests that APOE4 may represent a promising therapeutic target for reducing tau-associated neurodegeneration.

Parental age influences new genetic mutations in children

Older parents, and especially older fathers, tend to have children who show a higher number of mutations in their DNA, according to research, published in Nature. The researchers looked at the DNA of 1500 families in Iceland to see how changes in the DNA occurred in each generation and how parents’ age affected those changes. They found that the number of de novo genetic mutations (DNMs) per year of age of mothers increases by only a quarter of the rate of increase from fathers. These changes in DNA are a key driver of evolution and a source of rare genetic diseases, and occur during the formation of eggs and sperm. The researchers performed whole-genome sequence analysis of 14 688 Icelanders, including 1548 individuals and their parents, and, for 225 of these individuals, at least one of their children, to understand how the age and sex of parents may cause alterations in DNMs. The authors identified 108 778 high-quality DNMs, with an average of 70.3 DNMs per family. They found that the number of DNMs from mothers increases by 0.37 per year of age, compared with 1.51 per year of age increase from fathers. However, they also found that the number of clustered mutations increases faster with the mother’s age than the father’s, and the genomic span of maternal DNM clusters is greater than that of paternal ones. In addition, the types of DNMs from mothers change substantially with age.

Early human embryo development studied with CRISPR

The CRISPR–Cas9 genome-editing technique has been used to study the role of the OCT4 gene in early human embryo development, according to research published in Nature. The findings provide new insights into the molecular mechanisms that control embryogenesis and represent proof of principle that CRISPR–Cas9 genome editing can be used to evaluate gene function in early human development. During early human development, the zygote differentiates into a blastocyst comprising 200–300 cells that have distinct roles: some (known as pluripotent epiblast cells) go on to form the fetus, while others (extra-embryonic cells) contribute to the placenta and yolk sac. However, the mechanisms underlying these early “cell fate” decisions have remained unclear. OCT4 is a gene that is thought to be required for pluripotency and reprogramming in human cells, but whose function in early human embryos is poorly understood. Researchers from the UK and US used an optimised CRISPR-Cas9 genome editing approach to target OCT4 in human zygotes donated as surplus to infertility treatment. The authors show that OCT4 is required early in human development, and that when its expression is suppressed, blastocyst development is compromised. They also uncovered roles for OCT4 in regulating the expression of genes involved in the extra-embryonic cells that later form the placenta, and of pluripotent genes that define the epiblast. The authors concluded that their study provided a framework for future investigations that could further enhance our understanding of human embryo development, which could eventually lead to improvements in the development and therapeutic use of stem cells and in IVF (in vitro fertilisation) treatments.

Women with heart disease do worse than men

Women with coronary heart disease (CHD) are less likely to achieve treatment targets than men, according to an international study, published in Heart. The authors, including one from the George Institute for Global Health, said that a better understanding of sex disparities was needed to treat women with CHD more efficiently in all regions, especially in Asia and the Middle East. CHD remains one of the leading causes of death and disability worldwide. Despite convincing evidence on the benefits of managing risk factors in people with established CHD (eg, lowering blood pressure and cholesterol levels and being physically active), an unacceptably large proportion of affected individuals do not reach recommended risk factor targets. The researchers analysed data from just over 10 000 patients (29% women) with CHD from Europe, Asia and the Middle East between 2012 and 2013. On average, women were 4 years older than men. Adherence to guideline-recommended treatment and lifestyle targets was recorded as a Cardiovascular Health Index Score (CHIS). Overall, only 6% of women and 8% of men reached all treatment targets and about one-third of men and women met all lifestyle targets. After adjusting for several factors that could have influenced the results, they found that, compared with men, women were less likely to achieve targets for total cholesterol (8% v 14%), low-density lipoprotein cholesterol (22% v 33%) and blood glucose (71% v 76%), or to be physically active or non-obese. In contrast, women had better control of blood pressure (45% v 38%) and were more likely to be a non-smoker than men. Overall, women were less likely than men to achieve all treatment targets or obtain an adequate CHIS, but no significant differences were found for all lifestyle targets. Sex disparities in reaching treatment targets were smaller in Europe than in Asia and the Middle East. Women in Asia were more likely than men to reach all lifestyle targets, but the reverse was seen in Europe and the Middle East. The findings were similar after further adjusting for risk factors. The authors outlined some possible reasons for these differences. For example, women are more likely to be underdiagnosed and are less likely to take medication, such as statins, than men. They concluded that risk factor management for the secondary prevention of CHD was generally worse in women than in men, and the magnitude and direction of the sex differences varied by region, “suggesting the need for tailored strategies to reduce these inequalities and to improve the uptake of guideline-recommended care for the secondary prevention of CHD in both men and women”.

 

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