F-box proteins Pof3 and Pof1 regulate Wee1 degradation and mitotic entry in fission yeast.

The key cyclin-dependent kinase Cdk1 (Cdc2) promotes irreversible mitotic entry, mainly by activating the phosphatase Cdc25 while suppressing the tyrosine kinase Wee1. Wee1 needs to be downregulated at the onset of mitosis to ensure rapid activation of Cdk1. In human somatic cells, one mechanism of suppressing Wee1 activity is mediated by ubiquitylation-dependent proteolysis through the Skp1/Cul1/F-box protein (SCF) ubiquitin E3 ligase complex. This mechanism is believed to be conserved from yeasts to humans. So far, the best-characterized human F-box proteins involved in recognition of Wee1 are ß-TrCP (BTRCP) and Tome-1 (CDCA3). Although fission yeast Wee1 was the first identified member of its conserved kinase family, the F-box proteins involved in recognition and ubiquitylation of Wee1 have not been identified in this organism. In this study, our screen using Wee1-Renilla luciferase as the reporter revealed that two F-box proteins, Pof1 and Pof3, are required for downregulating Wee1 and are possibly responsible for recruiting Wee1 to SCF. Our genetic analyses supported a functional relevance between Pof1 and Pof3 and the rate of mitotic entry, and Pof3 might play a major role in this process.

The Impact of UNC5C Genetic Variations on Neuroimaging in Alzheimer's Disease.

UNC5C, which is a transmembrane receptor for netrin-1 to trigger the apoptosis, has been confirmed as a new risk factor for Alzheimer's disease (AD) recently. However, there is lack of the evidence on the brain structure associated with the polymorphisms of UNC5C in AD. The objective of this study is to investigate the influence of UNC5C loci on the neuroimaging of strategic regions of AD. In 812 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset, we explored the genotypes of UNC5C loci in the volumes of the hippocampus, parahippocampal gyrus, posterior cingulate gyrus, middle temporal and precuneus, and the thickness of the entorhinal cortex which are measured by magnetic resonance imaging (MRI). We also investigated the atrophy rate of above structures influenced by UNC5C loci using the longitudinal data. UNC5C loci were associated with the volume of right middle temporal (rs34585936 Pc = 0.0031). Meanwhile, the polymorphisms of UNC5C loci could alter the atrophy rate of strategic regions especially the left hippocampus (rs72672784 Pc = 0.0090; rs13120458 Pc = 0.0434; rs34875919 Pc = 0.0434) and right precuneus (rs72672784 Pc = 0.0068; rs2001246 Pc = 0.0055; rs74690179 Pc = 0.0055). UNC5C genotypes were significantly associated with the volume of the middle temporal on MRI; meanwhile, UNC5C loci could alter the atrophy of strategic regions of AD such as the hippocampus and precuneus. And the above effects of polymorphisms of UNC5C were more obvious in the population with the impaired cognition than those with the normal cognition.

Serum Iron, Zinc, and Copper Levels in Patients with Alzheimer's Disease: A Replication Study and Meta-Analyses.

To evaluate whether iron, zinc, and copper levels in serum are disarranged in Alzheimer's disease (AD), we performed meta-analyses of all studies on the topic published from 1984 to 2014 and contextually carried out a replication study in serum as well. Our meta-analysis results showed that serum zinc was significantly lower in AD patients. Our replication and meta-analysis results showed that serum copper was significantly higher in AD patients than in healthy controls, so our findings were consistent with the conclusions of four previously published copper meta-analyses. Even if a possible role of iron in the pathophysiology of the disease could not be ruled out, the results of our meta-analysis showed no change of serum iron levels in AD patients, but this conclusion was not robust and requires further investigation. The meta-regression analyses revealed that in some studies, differences in serum iron levels could be due to the different mean ages, while differences in zinc levels appeared to be due to the different sex ratios. However, the effect of sex ratio on serum zinc levels in our meta-analysis is subtle and needs further confirmation. Also, diverse demographic terms and methodological approaches appeared not to explain the high heterogeneity of our copper meta-analysis. Therefore, when investigating trace elements, covariants such as age and sex have to be taken into account in the analyses. In the light of these findings, we suggest that the possible alteration of serum zinc and copper levels are involved in the pathogenesis of AD.

Genetics of Vascular Dementia: Systematic Review and Meta-Analysis.

BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia. So far, little is known about the contribution of genetic polymorphisms to the risk of VaD. Many candidate genetic polymorphisms have been examined in a large number of studies. However, due to the conflicting results, the genetics of VaD is still behind the shadow. OBJECTIVE: We conducted a comprehensive meta-analysis on associations between genetic polymorphisms of any gene and VaD to investigate the genetics of VaD. METHOD: We sought the published studies of associations between any genetic polymorphism and VaD and critically appraised them. We assessed the effects of genetic models by calculating pooled odds ratios (ORs), investigating the origin of heterogeneity by subgroup analysis, and testing the robustness by random effect model and sensitivity analysis. RESULTS: 69 studies with 4,462 cases and 11,583 controls were included. We identified APOE ɛ2/ɛ3/ɛ4 and additional four genetic polymorphisms including MTHFR C677T, PON1 L55M, TGF-ß1 +29C/T, and TNF-α -850C/T associated with VaD. Tested by random effect model and sensitivity analysis, the pooled results show nice robustness. CONCLUSIONS: Our comprehensive meta-analysis highlighted the genetic contribution to sporadic VaD. Because of the small amount of data on associations between genetic polymorphisms, except for APOE, and VaD, more studies are needed to test the existing genetic polymorphisms and detect other related genetic variants.

The role of cholesterol metabolism in Alzheimer's disease.

Alzheimer's disease (AD) is the most common type of dementias and becoming a worldwide problem. As the time goes by, more and more researches show that AD is related to cholesterol in the brain. Both the Aß and the phosphorylated tau are believed to be the key factors in the pathogenesis of AD. Cholesterol in the brain is involved in a series of interdependent metabolism processes of Aß including the synthesis, aggregation, neurotoxicity, and elimination. The phosphorylated tau is also considered to be related to cholesterol metabolism. Besides that, there is evidence suggesting that cholesterol might contribute to the pathogenesis of AD by inducing the dysfunction of cerebral vessels such as the arteriosclerosis and cerebral amyloid angiopathy (CAA). In this review, we summarize our current understanding on the role of cholesterol in the pathogenesis of AD, and also propose the therapeutic research process on cholesterol-regulating drugs in the treatment of AD pathology.

Post-stroke cognitive impairment: epidemiology, mechanisms and management.

Post-stroke cognitive impairment occurs frequently in the patients with stroke. The prevalence of post-stroke cognitive impairment ranges from 20% to 80%, which varies for the difference between the countries, the races, and the diagnostic criteria. The risk of post-stroke cognitive impairment is related to both the demographic factors like age, education and occupation and vascular factors. The underlying mechanisms of post-stroke cognitive impairment are not known in detail. However, the neuroanatomical lesions caused by the stroke on strategic areas such as the hippocampus and the white matter lesions (WMLs), the cerebral microbleeds (CMBs) due to the small cerebrovascular diseases and the mixed AD with stroke, alone or in combination, contribute to the pathogenesis of post-stroke cognitive impairment. The treatment of post-stroke cognitive impairment may benefit not only from the anti-dementia drugs, but also the manage measures on cerebrovascular diseases. In this review, we will describe the epidemiological features and the mechanisms of post-stroke cognitive impairment, and discuss the promising management strategies for these patients.