Search

Background: Copy number variants (CNVs) have been reported to be associated with diseases, traits, and evolution. However, it is hard to determine which gene should have priority as a target for further functional experiments if a CNV is rare or a singleton. In this study, we attempted to overcome this issue by using two approaches: by assessing the influences of gene dosage sensitivity and gene expression sensitivity. Dosage sensitive genes derived from two-round whole-genome duplication in previous studies. In addition, we proposed a cross-sectional omics approach that utilizes open data from GTEx to assess the effect of whole-genome CNVs on gene expression., Methods: Affymetrix Genome-Wide SNP Array 6.0 was used to detect CNVs by PennCNV and CNV Workshop. After quality controls for population stratification, family relationship and CNV detection, 287 patients with narcolepsy, 133 patients with essential hypersomnia, 380 patients with panic disorders, 164 patients with autism, 784 patients with Alzheimer disease and 1280 healthy individuals remained for the enrichment analysis., Results: Overall, significant enrichment of dosage sensitive genes was found across patients with narcolepsy, panic disorders and autism. Particularly, significant enrichment of dosage-sensitive genes in duplications was observed across all diseases except for Alzheimer disease. For deletions, less or no enrichment of dosage-sensitive genes with deletions was seen in the patients when compared to the healthy individuals. Interestingly, significant enrichments of genes with expression sensitivity in brain were observed in patients with panic disorder and autism. While duplications presented a higher burden, deletions did not cause significant differences when compared to the healthy individuals. When we assess the effect of sensitivity to genome dosage and gene expression at the same time, the highest ratio of enrichment was observed in the group including dosage-sensitive genes and genes with expression sensitivity only in brain. In addition, shared CNV regions among the five neuropsychiatric diseases were also investigated., Conclusions: This study contributed the evidence that dosage-sensitive genes are associated with CNVs among neuropsychiatric diseases. In addition, we utilized open data from GTEx to assess the effect of whole-genome CNVs on gene expression. We also investigated shared CNV region among neuropsychiatric diseases.

The molecular biological mechanisms of Alzheimer's disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer's disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops., Methods: To characterize AD SNPs within non-coding regions, we extracted 406 AD SNPs with GWAS p-values of less than 1.00 × 10 - 6 from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments., Results: We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes., Conclusion: Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT : OR (odds ratio) = 27.02, p = 8.80 × 10 -94 ; GT : OR = 15.87, p = 2.62 × 10 -9 ) and EuroAs ( TT : OR = 18.13, p = 2.69 × 10 -108 ; GT : OR = 12.63, p = 3.44 × 10 -64 ), and rs405509- T homozygotes had a younger onset and more severe cortical atrophy than those with G -allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.

Objective: We aimed to identify modularized structural atrophy of brain regions with a high degree of connectivity and its longitudinal changes associated with the progression of Alzheimer's disease (AD) using weighted gene co-expression network analysis (WGCNA), which is an unsupervised hierarchical clustering method originally used in genetic analysis., Methods: We included participants with late mild cognitive impairment (MCI) at baseline from the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study. We imputed normalized and Z-transformed structural volume or cortical thickness data of 164 parcellated brain regions/structures based on the calculations of the FreeSurfer software. We applied the WGCNA to extract modules with highly interconnected structural atrophic patterns and examined the correlation between the identified modules and clinical AD progression., Results: We included 204 participants from the baseline dataset, and performed a follow-up with 100 in the 36-month dataset of MCI cohort participants from the J-ADNI. In the univariate correlation or variable importance analysis, baseline atrophy in temporal lobe regions/structures significantly predicted clinical AD progression. In the WGCNA consensus analysis, co-atrophy modules associated with MCI conversion were first distributed in the temporal lobe and subsequently extended to adjacent parietal cortical regions in the following 36 months., Conclusions: We identified coordinated modules of brain atrophy and demonstrated their longitudinal extension along with the clinical course of AD progression using WGCNA, which showed a good correspondence with previous pathological studies of the tau propagation theory. Our results suggest the potential applicability of this methodology, originating from genetic analyses, for the surrogate visualization of the underlying pathological progression in neurodegenerative diseases not limited to AD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Effect of serum calcium level to the incidence of mild cognitive impairment (MCI) conversion to early Alzheimer's disease (AD) remains uncertain., Objective: To investigate association between baseline serum calcium and the MCI conversion in the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) study cohort., Methods: In this sub-analysis of J-ADNI study, we reviewed data from MCI participants at baseline regarding their conversion to early AD during the 3 years of observation period and assessed the associated factors including serum calcium level. In addition, we compared our results from the J-ADNI study with the corresponding results from the North American (NA)-ADNI., Results: Of 234 eligible MCI participants from the J-ADNI cohort, 121 (51.7%) converted to AD during the first 36 months of observation. Using univariate analysis, being female, having shorter years of education, and lower serum calcium level were correlated with increased risk of MCI-to-AD conversion exclusively in J-ADNI cohort. The lower corrected serum calcium level remained as one of conversion-associated factors in the J-ADNI cohort even after adjustment for multiple confounding variables, although this was not observed in the NA-ADNI cohort., Conclusion: Our findings suggest that lower serum calcium may be associated with an increased risk of MCI conversion to AD in Japanese cohorts. The reason for this correlation remains unclear and further external validation using other Asian cohorts is needed. It would be interesting for future AD studies to obtain serum calcium levels and other related factors, such as vitamin D levels, culture-specific dietary or medication information.

Essential hypersomnia (EHS) is a lifelong disorder characterized by excessive daytime sleepiness without cataplexy. EHS is associated with human leukocyte antigen (HLA)-DQB1*06:02, similar to narcolepsy with cataplexy (narcolepsy). Previous studies suggest that DQB1*06:02-positive and -negative EHS are different in terms of their clinical features and follow different pathological pathways. DQB1*06:02-positive EHS and narcolepsy share the same susceptibility genes. In the present study, we report a genome-wide association study with replication for DQB1*06:02-negative EHS (408 patients and 2247 healthy controls, all Japanese). One single-nucleotide polymorphism, rs10988217, which is located 15-kb upstream of carnitine O-acetyltransferase (CRAT), was significantly associated with DQB1*06:02-negative EHS (P = 7.5 × 10 -9 , odds ratio = 2.63). The risk allele of the disease-associated SNP was correlated with higher expression levels of CRAT in various tissues and cell types, including brain tissue. In addition, the risk allele was associated with levels of succinylcarnitine (P = 1.4 × 10 -18 ) in human blood. The leading SNP in this region was the same in associations with both DQB1*06:02-negative EHS and succinylcarnitine levels. The results suggest that DQB1*06:02-negative EHS may be associated with an underlying dysfunction in energy metabolic pathways.

Introduction: The objective of this study was to determine the frequency and clinical and cognitive characteristics of preclinical Alzheimer's disease (AD) in a Japanese population to effectively design and conduct future preventive trials on preclinical AD., Methods: Three-year longitudinal data from cognitively normal participants who underwent cerebrospinal fluid biomarker measurement and/or amyloid positron emission tomography in the Japanese Alzheimer's Disease Neuroimaging Initiative, were analyzed. Comparisons between participants with and without amyloid β (Aβ) accumulation, and between those with and without elevated tau levels tau among participants with Aβ accumulation were performed., Results: Among 84 participants with available cerebrospinal fluid biomarker and/or amyloid positron emission tomography data, 19 (22.6%) exhibited Aβ accumulation. The frequency of APOE ε4 alleles was significantly higher in participants with Aβ accumulation. There were no significant differences in any of the cognitive tests at the baseline; however, participants with Aβ accumulation exhibited a decline in clock drawing test (linear mixed-effects model, P  = .008) and a tendency toward loss of practice effects in the Mini-Mental State Examination and the logical memory over time. Although it did not reach statistical significance, the analysis indicated a decline in measurements of executive function over time in participants with elevated tau levels compared with those with normal tau levels., Discussion: The frequency of preclinical AD in the Japanese Alzheimer's Disease Neuroimaging Initiative was lower than in similar studies because of the younger age of the participants and lower frequency of APOE ε4 carriage. Although limitations in sample size precluded definitive conclusions, the results suggest that even in the preclinical phase of AD, loss of practice effects in episodic memory tests and at a later stage, decline in executive function, are present. These findings may be useful for recruitment of individuals with preclinical AD and establishing a novel cognitive composite for use in clinical trials on preclinical AD.

Introduction: We conducted Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) and compared the basic characteristics and progression profiles with those of ADNI in North America., Methods: A total of 537 Japanese subjects with normal cognition, late amnestic mild cognitive impairment (LMCI), or mild Alzheimer's disease (AD) were enrolled using the same criteria as ADNI. Rates of changes in representative cognitive or functional measures were compared for amyloid positron emission tomography- or cerebrospinal fluid amyloid β(1-42)-positive LMCI and mild AD between J-ADNI and ADNI., Results: Amyloid positivity rates were significantly higher in normal cognition of ADNI but at similar levels in LMCI and mild AD between J-ADNI and ADNI. Profiles of decline in cognitive or functional measures in amyloid-positive LMCI in J-ADNI (n = 75) and ADNI (n = 269) were remarkably similar, whereas those in mild AD were milder in J-ADNI (n = 73) compared with ADNI (n = 230)., Discussion: These results support the feasibility of bridging of clinical trials in the prodromal stage of AD between Asia and western countries., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The objective of this study was to determine whether sex or education level affects the longitudinal rate of cognitive decline in Japanese patients in the Alzheimer's disease Neuroimaging Initiative study with defined mild cognitive impairment (MCI)., Methods: We accessed the entire Japanese Alzheimer's Disease Neuroimaging Initiative data set of 537 individuals, among whom 234 had MCI and 149 had Alzheimer's disease. We classified participants into three categories of educational history: (1) low, 0 to 9 years; (2) moderate, 10 to 15 years; and (3) high ≥16 years. We examined the main effects and interactions of visit, sex, and educational achievement on scores for the Clinical Dementia Rating Sum of Boxes, Alzheimer's Disease Assessment Scale-cognitive subscale 13, Mini-Mental State Examination, and Functional Activities Questionnaire in a longitudinal manner., Results: Women with MCI had a significantly faster rate of decline than men over a 3-year period. Highly educated men showed a significantly slower rate of decline than the other groups. Sex differences in the rates of decline remained after stratification by amyloid or apolipoprotein E ( APOE ) ε4 status but were absent in Alzheimer's disease over a 2-year period. Subtle differences in chronic kidney disease grade affected the rate of decline. A higher Fazekas periventricular hyperintensity score was associated with a lower estimated glomerular filtration rate in women only., Discussion: In patients with MCI, sex and educational history significantly affected the rate of change in cognitive and clinical assessments. Furthermore, a subtle decline in chronic kidney disease grade was associated with a faster rate of decline regardless of amyloid pathology in women.

A chemoselective hydrogenation of isoquinoline carbocycles was achieved by using the catalyst prepared from Ru(methallyl) 2 (cod) and trans-chelate chiral ligand PhTRAP. The unique chemoselectivity achieved in this hydrogenation could be ascribed to the trans-chelation of the chiral ligand. The procedure for preparing the catalyst strongly affects the reproducibility of the carbocycle hydrogenation. Various 5-, 6-, 7-, and 8-substituted isoquinolines were selectively hydrogenated at their carbocycles to afford 5,6,7,8-tetrahydroisoquinolines as major products in high yields with moderate or good enantioselectivities. Some mechanistic studies suggested that the stereogenic center was created during the initial addition of H 2 to the aromatic ring in the hydrogenation of 5-substituted isoquinolines. In other words, the stereochemical control was accompanied by the dearomatization.

Aim: Evidence for the association between dialysis treatment and cognitive decline is limited. The present study aimed to determine whether dialysis treatment is associated with cognitive decline in adult outpatients of a general hospital in Japan., Methods: This was a cross-sectional substudy of the Project in Sado for Total Health (PROST). Total Health PROST targeted adult outpatients of a general hospital in Sado City, Niigata, Japan. Among 753 patients (mean age 68.1 ± 11.6 years) analyzed, 66 received dialysis. Cognitive state was evaluated using the Mini-Mental State Examination, and those with a Mini-Mental State Examination score <24 were considered "cognitively declined." The prevalence of cognitive decline was compared by odds ratios calculated with multiple logistic regression analysis. Variables included in the analyses were dialysis, age, sex and self-reported histories of hypertension, diabetes, stroke and ischemic heart disease., Results: Of the 66 dialysis patients, 24 (36.4%) showed cognitive decline, whereas 172 (25.0%) of 687 non-dialysis patients showed cognitive decline. The age and sex-adjusted odds ratio for cognitive decline in dialysis patients was 2.57 (95% confidence interval 1.43-4.61), relative to non-dialysis patients. The odds ratio remained significant (odds ratio 2.69, 95% confidence interval 1.49-4.88) even after adjusting for all covariates., Conclusion: The prevalence of cognitive decline was high in dialysis patients relative to non-dialysis patients among outpatients of a general hospital in Japan. Geriatr Gerontol Int 2017; 17: 1584-1587., (© 2016 Japan Geriatrics Society.)

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood., Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset., Results: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10 -8 ) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10 -6 ) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10 -6 )., Discussion: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin-positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondrial function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as K V 3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 ( Oxr1 ), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2-deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

MicroRNAs (miRNAs) are attractive molecules to utilize as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer's disease (AD) because miRNAs are relatively stable in biofluid, including serum or plasma. To determine blood miRNA biomarkers for AD with next-generation sequencing genome-wide, we first surveyed 45 serum samples. These came from 27 AD patients and 18 controls (discovery set) that underwent autopsy within two weeks after their serum sampling and were neuropathologically diagnosed. We found that three miRNAs, hsa-miR-501-3p, hsa-let-7f-5p, and hsa-miR-26b-5p, were significantly deregulated between the AD samples and the controls. The deregulation for hsa-miR-501-3p was further confirmed by quantitative reverse transcription polymerase chain reaction (PCR) in a validation set composed of 36 clinically diagnosed AD patients and 22 age-matched cognitively normal controls with a sensitivity and specificity of 53% and 100%, respectively (area under the curve = 0.82). Serum hsa-miR-501-3p levels were downregulated in AD patients, and its lower levels significantly correlated with lower Mini-Mental State Examination scores. Contrary to its serum levels, we found that hsa-miR-501-3p was remarkably upregulated in the same donors' AD brains obtained at autopsy from the discovery set. The hsa-miR-501-3p overexpression in cultured cells, which mimicked the hsa-miR-501-3p upregulation in the AD brains, induced significant downregulation of 128 genes that overrepresented the Gene Ontology terms, DNA replication, and the mitotic cell cycle. Our results suggest that hsa-miR-501-3p is a novel serum biomarker that presumably corresponds to pathological events occurring in AD brains.

Background: Little is known about the sample sizes required for clinical trials of Alzheimer's disease (AD)-modifying treatments using atrophy measures from serial brain magnetic resonance imaging (MRI) in the Japanese population., Objective: The primary objective of the present study was to estimate how large a sample size would be needed for future clinical trials for AD-modifying treatments in Japan using atrophy measures of the brain as a surrogate biomarker., Methods: Sample sizes were estimated from the rates of change of the whole brain and hippocampus by the k-means normalized boundary shift integral (KN-BSI) and cognitive measures using the data of 537 Japanese Alzheimer's Neuroimaging Initiative (J-ADNI) participants with a linear mixed-effects model. We also examined the potential use of ApoE status as a trial enrichment strategy., Results: The hippocampal atrophy rate required smaller sample sizes than cognitive measures of AD and mild cognitive impairment (MCI). Inclusion of ApoE status reduced sample sizes for AD and MCI patients in the atrophy measures., Conclusion: These results show the potential use of longitudinal hippocampal atrophy measurement using automated image analysis as a progression biomarker and ApoE status as a trial enrichment strategy in a clinical trial of AD-modifying treatment in Japanese people.

In humans, narcolepsy is a sleep disorder that is characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities. Essential hypersomnia (EHS) is another type of sleep disorder that is characterized by excessive daytime sleepiness without cataplexy. A human leukocyte antigen (HLA) class II allele, HLA-DQB1*06:02, is a major genetic factor for narcolepsy. Almost all narcoleptic patients are carriers of this HLA allele, while 30-50% of EHS patients and 12% of all healthy individuals in Japan carry this allele. The pathogenesis of narcolepsy and EHS is thought to be partially shared. To evaluate the contribution of common single-nucleotide polymorphisms (SNPs) to narcolepsy onset and to assess the common genetic background of narcolepsy and EHS, we conducted a polygenic analysis that included 393 narcoleptic patients, 38 EHS patients with HLA-DQB1*06:02, 119 EHS patients without HLA-DQB1*06:02 and 1582 healthy individuals. We also included 376 individuals with panic disorder and 213 individuals with autism to confirm whether the results were biased. Polygenic risks in narcolepsy were estimated to explain 58.1% (P HLA-DQB1*06:02 =2.30 × 10 -48 , P whole genome without HLA-DQB1*06:02 =6.73 × 10 -2 ) including HLA-DQB1*06:02 effects and 1.3% (P whole genome without HLA-DQB1*06:02 =2.43 × 10 -2 ) excluding HLA-DQB1*06:02 effects. The results also indicated that small-effect SNPs contributed to the development of narcolepsy. Reported susceptibility SNPs for narcolepsy in the Japanese population, CPT1B (carnitine palmitoyltransferase 1B), TRA@ (T-cell receptor alpha) and P2RY11 (purinergic receptor P2Y, G-protein coupled, 11), were found to explain 0.8% of narcolepsy onset (P whole genome without HLA-DQB1*06:02 =9.74 × 10 -2 ). EHS patients with HLA-DQB1*06:02 were estimated to have higher shared genetic background to narcoleptic patients than EHS patients without HLA-DQB1*06:02 even when the effects of HLA-DQB1*06:02 were excluded (EHS with HLA-DQB1*06:02: 40.4%, P HLA-DQB1*06:02 =7.02 × 10 - 14 , P whole genome without HLA-DQB1*06:02 =1.34 × 10 - 1 , EHS without HLA-DQB1*06:02: 0.4%, P whole genome without HLA-DQB1*06:02 =3.06 × 10 - 1 ). Meanwhile, the polygenic risks for narcolepsy could not explain the onset of panic disorder and autism, suggesting that our results were reasonable.

High enantioselectivity was achieved for the hydrogenation of azaindoles by using the chiral catalyst, which was prepared from [Ru(η(3) -methallyl)2 (cod)] and a trans-chelating bis(phosphine) ligand (PhTRAP). The dearomative reaction exclusively occurred on the five-membered ring, thus giving the corresponding azaindolines with up to 97:3 enantiomer ratio., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Mutations in the coding sequence of SCN5A, which encodes the cardiac Na(+) channel α subunit, have been associated with inherited susceptibility to various arrhythmias. Variable expression of SCN5A is a possible mechanism responsible for this pleiotropic effect; however, it is unknown whether variants in the promoter and regulatory regions of SCN5A also modulate the risk of arrhythmias., Methods and Results: We resequenced the core promoter region of SCN5A and the regulatory regions of SCN5A transcription in 1298 patients with arrhythmia phenotypes (atrial fibrillation, n=444; sinus node dysfunction, n=49; conduction disease, n=133; Brugada syndrome, n=583; and idiopathic ventricular fibrillation, n=89). We identified 26 novel rare variants in the SCN5A promoter in 29 patients affected by various arrhythmias (atrial fibrillation, n=6; sinus node dysfunction, n=1; conduction disease, n=3; Brugada syndrome, n=14; idiopathic ventricular fibrillation, n=5). The frequency of rare variants was higher in patients with arrhythmias than in controls. In the alignment with chromatin immunoprecipitation sequencing data, the majority of variants were located at regions bound by transcription factors. Using a luciferase reporter assay, 6 variants (Brugada syndrome, n=3; idiopathic ventricular fibrillation, n=2; conduction disease, n=1) were functionally characterized, and each displayed decreased promoter activity compared with the wild-type sequences. We also identified rare variants in the regulatory region that were associated with atrial fibrillation, and the variant decreased promoter activity., Conclusions: Variants in the core promoter region and the transcription regulatory region of SCN5A were identified in multiple arrhythmia phenotypes, consistent with the idea that altered SCN5A transcription levels modulate susceptibility to arrhythmias., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background/aims: Evidence on modifiable factors associated with cognitive impairment in Japanese patients is scarce. This study aimed to determine modifiable factors for cognitive impairment in a Japanese hospital-based population., Methods: Subjects of this cross-sectional study were 1,143 patients of Sado General Hospital (Niigata, Japan) registered in the Project in Sado for Total Health (PROST) between June 2008 and September 2014. We assessed disease history, body mass index (BMI), leisure time physical activity, walking time, smoking and drinking habits, and consumption of vegetables, fruits, and green tea as predictors, with cognitive impairment defined by the Mini-Mental State Examination (score <24) as an outcome. Multiple logistic regression analysis was performed to calculate odds ratios (ORs) for cognitive impairment., Results: The mean subject age was 68.9 years, and the prevalence of cognitive impairment was 21.5%. Multivariate analysis revealed that age (p < 0.001), low BMI (<21.1; OR 1.39, 95% CI 1.12-1.72), a history of stroke (p = 0.003), a history of myocardial infarction (p = 0.038), low fruit consumption (p for trend = 0.012), and low green tea consumption (p for trend = 0.032) were independently associated with a higher prevalence of cognitive impairment., Conclusions: Modifiable factors, such as low BMI, low fruit consumption, and low green tea consumption, are associated with cognitive impairment. Longitudinal studies will be needed to confirm these findings.

The iridium catalyst [IrCl(cod)]2 -phosphine-I2 (cod=1,5-cyclooctadiene) selectively reduced isoxazolium triflates to isoxazolines or isoxazolidines in the presence of H2 . The iridium-catalyzed hydrogenation proceeded in high-to-good enantioselectivity when an optically active phosphine-oxazoline ligand was used. The 3-substituted 5-arylisoxazolium salts were transformed into 4-isoxazolines with up to 95:5 enantiomeric ratio (e.r.). Chiral cis-isoxazolidines were obtained in up to 89:11 e.r., with no formation of their trans isomers, when the substrates had a primary alkyl substituent at the 5-position. The mechanistic studies indicate that the hydridoiridium(III) species prefers to deliver its hydride to the C5 atom of the isoxazole ring. The hydride attack leads to the formation of the chiral isoxazolidine via a 3-isoxazoline intermediate. Meanwhile, in the selective formation of 4-isoxazolines, hydride attack at the C5 atom may be obstructed by steric hindrance from the 5-aryl substituent., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: To elucidate the molecular mechanism of mutant HTRA1-dependent cerebral small vessel disease in heterozygous individuals., Methods: We recruited 113 unrelated index patients with clinically diagnosed cerebral small vessel disease. The coding sequences of the HTRA1 gene were analyzed. We evaluated HTRA1 protease activities using casein assays and oligomeric HTRA1 formation using gel filtration chromatography., Results: We found 4 heterozygous missense mutations in the HTRA1 gene (p.G283E, p.P285L, p.R302Q, and p.T319I) in 6 patients from 113 unrelated index patients and in 2 siblings in 2 unrelated families with p.R302Q. The mean age at cognitive impairment onset was 51.1 years. Spondylosis deformans was observed in all cases, whereas alopecia was observed in 3 cases; an autopsied case with p.G283E showed arteriopathy in their cerebral small arteries. These mutant HTRA1s showed markedly decreased protease activities and inhibited wild-type HTRA1 activity, whereas 2 of 3 mutant HTRA1s reported in cerebral autosomal-recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (A252T and V297M) did not inhibit wild-type HTRA1 activity. Wild-type HTRA1 forms trimers; however, G283E and T319I HTRA1, observed in manifesting heterozygotes, did not form trimers. P285L and R302Q HTRA1s formed trimers, but their mutations were located in domains that are important for trimer-associated HTRA1 activation; in contrast, A252T and V297M HTRA1s, which have been observed in CARASIL, also formed trimers but had mutations outside the domains important for trimer-associated HTRA1 activation., Conclusions: The mutant HTRA1s observed in manifesting heterozygotes might result in an impaired HTRA1 activation cascade of HTRA1 or be unable to form stable trimers., (© 2016 American Academy of Neurology.)

We herein report an association between TMEM132D and panic disorder (PD) in a Japanese population, evaluating the effects of HLA-DRB1*13:02, which we previously reported as a susceptibility genetic factor for PD. SNPs in TMEM132D showed significant associations with PD in subjects without HLA-DRB1*13:02 (rs4759997; P=5.02×10(-6), odds ratio=1.50) but not in those with the HLA allele. TMEM132D might have a role in the development of PD in subjects without HLA-DRB1*13:02.

Background/aims: We aimed to determine whether the concentration of serum C-reactive protein (CRP) is associated with cognitive function in an adult Japanese population., Methods: Participants of this cross-sectional study were from a subgroup of the Project in Sado for Total Health (PROST; n = 454; mean age, 70.5 years). The cognitive state was evaluated using the Mini-Mental State Examination (MMSE), and those with an MMSE score <24 were considered 'cognitively declined'. Concentrations of serum high-sensitivity CRP were measured. Multiple logistic regression analysis was used to calculate odds ratios (ORs) for cognitive decline, adjusting for the covariates of age, sex, BMI, disease history, and APOE allele., Results: Of the 454 participants, 94 (20.7%) were cognitively declined. Relative to the lowest (first) quartile of CRP concentration, adjusted ORs were 1.29 (95% CI 0.61-2.75) for the second, 1.78 (95% CI 0.82-3.86) for the third, and 3.05 (95% CI 1.45-6.42) for the highest (fourth) quartiles (p for trend = 0.018). When data were stratified by sex, the association between CRP concentration and cognitive decline was observed only in women., Conclusion: Our findings suggest an association between higher CRP concentration and lower cognitive function. Chronic inflammation may affect cognitive function in adults, in particular women.

Alzheimer's disease (AD) is a complex neurodegenerative disorder in which loss of neurons and synaptic function causes dementia in the elderly. To clarify AD pathogenesis and develop drugs for AD, thousands of studies have elucidated signaling pathways involved. However, knowledge of AD signaling pathways has not been compiled as a pathway map. In this chapter, we introduce the manual construction of a pathway map in AD which we call "AlzPathway", that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built the AD pathway map. AlzPathway is currently composed of thousands of molecules and reactions in neurons, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells, with their cellular localizations. AlzPathway provides a systems-biology platform of comprehensive AD signaling and related pathways which is expected to contribute to clarification of AD pathogenesis and AD drug development.

Alzheimer's disease (AD) is known to be a multifactorial neurodegenerative disorder, and is one of the main causes of dementia in the elderly. Many studies have demonstrated molecules involved in the pathogenesis of AD, however its underlying mechanisms remain obscure. It may be simplistic to try to explain the disease based on the role of a few genes only. Accumulating new, huge amount of information from e.g. genome, proteome and interactome datasets and new knowledge, we are now able to clarify and characterize diseases essentially as a result of dysfunction of molecular networks. Recent studies have indicated that relevant genes affected in human diseases concentrate in a part of the network, often called as "disease module." In the case of AD, some disease-associated pathways seem different, but some of them are clearly disease-related and coherent. This suggests the existence of a common pathway that negatively drives from healthy state to disease state (i.e., the disease module(s)). Additionally, such disease modules should dynamically change through AD progression. Thus, network-level approaches are indispensable to address unknown mechanisms of AD. In this chapter, we introduce network strategies using gene co-expression and protein interaction networks.

Etiology of narcolepsy-cataplexy involves multiple genetic and environmental factors. While the human leukocyte antigen (HLA)-DRB1*15:01-DQB1*06:02 haplotype is strongly associated with narcolepsy, it is not sufficient for disease development. To identify additional, non-HLA susceptibility genes, we conducted a genome-wide association study (GWAS) using Japanese samples. An initial sample set comprising 409 cases and 1562 controls was used for the GWAS of 525,196 single nucleotide polymorphisms (SNPs) located outside the HLA region. An independent sample set comprising 240 cases and 869 controls was then genotyped at 37 SNPs identified in the GWAS. We found that narcolepsy was associated with a SNP in the promoter region of chemokine (C-C motif) receptor 1 (CCR1) (rs3181077, P=1.6×10(-5), odds ratio [OR]=1.86). This rs3181077 association was replicated with the independent sample set (P=0.032, OR=1.36). We measured mRNA levels of candidate genes in peripheral blood samples of 38 cases and 37 controls. CCR1 and CCR3 mRNA levels were significantly lower in patients than in healthy controls, and CCR1 mRNA levels were associated with rs3181077 genotypes. In vitro chemotaxis assays were also performed to measure monocyte migration. We observed that monocytes from carriers of the rs3181077 risk allele had lower migration indices with a CCR1 ligand. CCR1 and CCR3 are newly discovered susceptibility genes for narcolepsy. These results highlight the potential role of CCR genes in narcolepsy and support the hypothesis that patients with narcolepsy have impaired immune function., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Cytogenomic mutations and chromosomal abnormality are implicated in the neuropathology of several brain diseases. Cell heterogeneity of brain tissues makes their detection and validation difficult, however. In the present study, we analyzed gene dosage alterations in brain DNA of schizophrenia patients and compared those with the copy number variations (CNVs) identified in schizophrenia patients as well as with those in Asian lymphocyte DNA and attempted to obtain hints at the pathological contribution of cytogenomic instability to schizophrenia., Results: Brain DNA was extracted from postmortem striatum of schizophrenia patients and control subjects (n = 48 each) and subjected to the direct two color microarray analysis that limits technical data variations. Disease-associated biases of relative DNA doses were statistically analyzed with Bonferroni's compensation on the premise of brain cell mosaicism. We found that the relative gene dosage of 85 regions significantly varied among a million of probe sites. In the candidate CNV regions, 26 regions had no overlaps with the common CNVs found in Asian populations and included the genes (i.e., ANTXRL, CHST9, DNM3, NDST3, SDK1, STRC, SKY) that are associated with schizophrenia and/or other psychiatric diseases. The majority of these candidate CNVs exhibited high statistical probabilities but their signal differences in gene dosage were less than 1.5-fold. For test evaluation, we rather selected the 10 candidate CNV regions that exhibited higher aberration scores or larger global effects and were thus confirmable by PCR. Quantitative PCR verified the loss of gene dosage at two loci (1p36.21 and 1p13.3) and confirmed the global variation of the copy number distributions at two loci (11p15.4 and 13q21.1), both indicating the utility of the present strategy. These test loci, however, exhibited the same somatic CNV patterns in the other brain region., Conclusions: The present study lists the candidate regions potentially representing cytogenomic CNVs in the brain of schizophrenia patients, although the significant but modest alterations in their brain genome doses largely remain to be characterized further.

The reduction of quinolines selectively took place on their carbocyclic rings to give 5,6,7,8-tetrahydroquinolines, when the hydrogenation was conducted in the presence of a Ru(η(3)-methallyl)2(cod)-PhTRAP catalyst. The chiral ruthenium catalyst converted 8-substituted quinolines into chiral 5,6,7,8-tetrahydroquinolines with up to 91 : 9 er.

Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD pedigrees with mutations have been reported in the Japanese population; however, it remains unclear whether the genetic and clinical features of FAD in the Japanese population differ from those in other populations. To address this issue, we conducted a systematic review and meta-analysis of Japanese FAD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) by literature search. Using this analysis, we identified 39 different PSEN1 mutations in 140 patients, 5 APP mutations in 35 patients and 16 MAPT mutations in 84 patients. There was no PSEN2 mutation among Japanese patients. The age at onset in Japanese FAD patients with PSEN1 mutations was significantly younger than that in patients with APP mutations. Kaplan-Meier analysis revealed that patients with MAPT mutations showed a shorter survival than patients with PSEN1 or APP mutations. Patients with mutations in different genes exhibit characteristic clinical presentations, suggesting that mutations in causative genes may modify the clinical presentations. By collecting and cataloging genetic and clinical information on Japanese FAD and FTDP-17, we developed an original database designated as Japanese Familial Alzheimer's Disease Database, which is accessible at http://alzdb.bri.niigata-u.ac.jp/.

Panic disorder (PD) is an anxiety disorder characterized by panic attacks and anticipatory anxiety. Both genetic and environmental factors are thought to trigger PD onset. Previously, we performed a genome-wide association study (GWAS) for PD and focused on candidate SNPs with the lowest P values. However, there seemed to be a number of polymorphisms which did not reach genome-wide significance threshold due to their low allele frequencies and odds ratios, even though they were truly involved in pathogenesis. Therefore we performed pathway analyses in order to overcome the limitations of conventional single-marker analysis and identify associated SNPs with modest effects. Each pathway analysis indicated that pathways related to immunity showed the strongest association with PD (DAVID, P=2.08×10(-6); i-GSEA4GWAS, P<10(-3); ICSNPathway, P<10(-3)). Based on the results of pathway analyses and the previously performed GWAS for PD, we focused on and investigated HLA-B and HLA-DRB1 as candidate susceptibility genes for PD. We typed HLA-B and HLA-DRB1 in 744 subjects with PD and 1418 control subjects. Patients with PD were significantly more likely to carry HLA-DRB1(∗)13:02 (P=2.50×10(-4), odds ratio=1.54). Our study provided initial evidence that HLA-DRB1(∗)13:02 and genes involved in immune-related pathways are associated with PD. Future studies are necessary to confirm these results and clarify the underlying mechanisms causing PD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The p.E66Q variant of the α-galactosidase A gene (GLA) is frequently found during screening for Fabry disease in dialysis patients in Japan. However, recent reports suggest that the p.E66Q variant is not a disease-causing mutation but is a risk factor for cerebral small-vessel occlusion. To evaluate the role of the p.E66Q in the progression of renal diseases, we performed a genetic association study in patients with chronic kidney disease (CKD)., Methods: In this study, we enrolled 1651 chronic hemodialysis and 941 non-dialysis patients who attended medical institutions in the Niigata Prefecture, Japan. The frequency of the p.E66Q allele was compared between hemodialysis and non-dialysis patients, with data from a previously published study of Japanese male newborns. In addition, we compared estimated glomerular filtration rates (eGFR) in the presence or absence of the p.E66Q variant in non-dialysis patients., Results: Of the 2233 alleles in hemodialysis and 1447 alleles in non-dialysis patients, 21 and nine harbored p.E66Q, respectively. However, p.E66Q allele frequencies did not differ between the two patient groups (0.90 versus 0.62 %, P = 0.35), and no significant difference in p.E66Q allele frequency was observed between male hemodialysis patients and the general Japanese population (0.52 versus 0.63 %, P = 0.67). Moreover, eGFR did not significantly differ between non-dialysis patients with the p.E66Q variant and patients with the wild-type allele (65.5 ± 10.7 versus 62.7 ± 16.6 mL/min/1.73 m(2), P = 0.69)., Conclusion: This study indicated that the p.E66Q variant of GLA does not affect the progression of CKD.

Background: We here examined whether plasma desmosterol-to-cholesterol ratio (DES/CHO) is decreased in patients with Alzheimer's disease (AD) and investigated the association between plasma DES/CHO and longitudinal cognitive decline., Methods: Plasma DES/CHO of AD patients and age-matched controls in a Japanese cross-sectional cohort was determined. Plasma DES/CHO at baseline and follow-up visits was assessed in relation to cognitive decline in Japanese and Swedish longitudinal cohorts., Results: Plasma DES/CHO was significantly reduced in Japanese AD patients and significantly correlated with Mini-Mental State Examination (MMSE) score. The longitudinal analysis revealed that plasma DES/CHO in AD patients shows a significant decrease at follow-up intervals. The decline in plasma DES/CHO is larger in the AD group with rapid progression than in that with slow progression. The changes in plasma DES/CHO significantly correlated with changes in the MMSE score., Conclusion: Plasma DES/CHO is decreased in AD patients and may serve as a longitudinal surrogate marker associated with cognitive decline.

The asymmetric hydrogenation of pyrimidines proceeded with high enantioselectivity (up to 99% ee) using an iridium catalyst composed of [IrCl(cod)]2, a ferrocene-containing chiral diphosphine ligand (Josiphos), iodine, and Yb(OTf)3 (cod = 1,5-cyclooctadiene). The chiral catalyst converted various 4-substituted pyrimidines into chiral 1,4,5,6-tetrahydropyrimidines in high yield. The lanthanide triflate is crucial for achieving the high enantioselectivity as well as for activating the heteroarene substrate., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A 59-year-old woman developed early-onset, slowly progressive dementia and spastic paraplegia. positron emission tomography (PET) imaging revealed a large reduction in the level of glucose uptake without amyloid deposition in the cerebral cortex. We identified a homozygous microdeletion within the amyloid β (Aβ) coding sequence in the amyloid precursor protein (APP) gene (c.2080&#95;2082delGAA, p.E693del) in three affected siblings and a heterozygous microdeletion in an unaffected sibling. The identical mutation was previously reported in the first Alzheimer's pedigree without amyloid deposits. Furthermore, an increase in high-molecular-weight Aβ-reactive bands was detected in the patient's CSF. Our findings suggest that soluble Aβ-oligomers induce neuronal toxicity, independent of insoluble Aβ fibrils.

Objective: Much of the genetic basis for Alzheimer disease (AD) is unexplained. We sought to identify novel AD loci using a unique family-based approach that can detect robust associations with infrequent variants (minor allele frequency < 0.10)., Methods: We conducted a genome-wide association study in the Framingham Heart Study (discovery) and NIA-LOAD (National Institute on Aging-Late-Onset Alzheimer Disease) Study (replication) family-based cohorts using an approach that accounts for family structure and calculates a risk score for AD as the outcome. Links between the most promising gene candidate and AD pathogenesis were explored in silico as well as experimentally in cell-based models and in human brain., Results: Genome-wide significant association was identified with a PLXNA4 single nucleotide polymorphism (rs277470) located in a region encoding the semaphorin-3A (SEMA3A) binding domain (meta-analysis p value [meta-P] = 4.1 × 10(-8) ). A test for association with the entire region was also significant (meta-P = 3.2 × 10(-4) ). Transfection of SH-SY5Y cells or primary rat neurons with full-length PLXNA4 (TS1) increased tau phosphorylation with stimulated by SEMA3A. The opposite effect was observed when cells were transfected with shorter isoforms (TS2 and TS3). However, transfection of any isoform into HEK293 cells stably expressing amyloid β (Aβ) precursor protein (APP) did not result in differential effects on APP processing or Aβ production. Late stage AD cases (n = 9) compared to controls (n = 5) had 1.9-fold increased expression of TS1 in cortical brain tissue (p = 1.6 × 10(-4) ). Expression of TS1 was significantly correlated with the Clinical Dementia Rating score (ρ = 0.75, p = 2.2 × 10(-4) ), plaque density (ρ = 0.56, p = 0.01), and Braak stage (ρ = 0.54, p = 0.02)., Interpretation: Our results indicate that PLXNA4 has a role in AD pathogenesis through isoform-specific effects on tau phosphorylation., (© 2014 American Neurological Association.)

The spreading of neurofibrillary tangles (NFTs), intraneuronal aggregates of highly phosphorylated microtubule-associated protein tau, across the human brain is correlated with the cognitive severity of Alzheimer's disease (AD). To identify genes relevant to NFT expansion defined by the Braak stage, we conducted whole-genome exon array analysis with an exploratory sample set consisting of 213 human post-mortem brain tissue specimens from the entorinal, temporal and frontal cortices of 71 brain-donor subjects: Braak NFT stages 0 (N=13), I-II (N=20), III-IV (N=19) and V-VI (N=19). We identified eight genes, RELN, PTGS2, MYO5C, TRIL, DCHS2, GRB14, NPAS4 and PHYHD1, associated with the Braak stage. The expression levels of three genes, PHYHD1, MYO5C and GRB14, exhibited reproducible association on real-time quantitative PCR analysis. In another sample set, including control subjects (N=30), and in patients with late-onset AD (N=37), dementia with Lewy bodies (N=17) and Parkinson disease (N=36), the expression levels of two genes, PHYHD1 and MYO5C, were obviously associated with late-onset AD. Protein-protein interaction network analysis with a public database revealed that PHYHD1 interacts with MYO5C via POT1, and PHYHD1 directly interacts with amyloid beta-peptide 42. It is thus likely that functional failure of PHYHD1 and MYO5C could lead to AD development.

Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.

Background: Presenilin 1 (PS1) mutations associated with familial Alzheimer disease (FAD) generally increase the amyloid-β 42 (Aβ42) to Aβ40 ratio secreted in cultured cells. Some of these mutants reduce the secretion of Aβ40 rather than increase that of Aβ42. Since it has been difficult to estimate Aβ42 secretion in brains of PS1-FAD patients due to substantial Aβ42 accumulation, it remains unknown whether the enhanced Aβ42 to Aβ40 ratio in brains of FAD patients is caused by elevated Aβ42 secretion or by reduced secretion of Aβ40., Objective/methods: Cerebrospinal fluids (CSF) of PS1-FAD patients and neurological control patients (controls) were collected. Levels of CSF amyloid precursor-like protein-1-derived Aβ-like peptide (APL1β), including APL1β28, an Aβ42 surrogate marker, were quantified by liquid chromatography tandem mass spectrometry, and Aβ42 secretion in the brain was estimated., Results: The relative ratio of CSF APL1β28 to total APL1β was higher in PS1-FAD patients than in controls. Importantly, CSF APL1β28 was not significantly higher. However, C-terminally shorter CSF APL1β25 and APL1β27 were significantly lower in PS1-FAD patients and, as expected, so were CSF Aβ40 and Aβ42., Conclusion: A higher relative ratio of the CSF Aβ42 surrogate in PS1-FAD patients is not due to its increase in CSF, suggesting that massive Aβ42 accumulation in the PS1-FAD brain occurs without an apparent increase in Aβ42 secretion.

Alzheimer's disease (AD), the most common cause of dementia, is associated with aging, and it leads to neuron death. Deposits of amyloid β and aberrantly phosphorylated tau protein are known as pathological hallmarks of AD, but the underlying mechanisms have not yet been revealed. A high-throughput gene expression analysis previously showed that differentially expressed genes accompanying the progression of AD were more down-regulated than up-regulated in the later stages of AD. This suggested that the molecular networks and their constituent modules collapsed along with AD progression. In this study, by using gene expression profiles and protein interaction networks (PINs), we identified the PINs expressed in three brain regions: the entorhinal cortex (EC), hippocampus (HIP) and superior frontal gyrus (SFG). Dividing the expressed PINs into modules, we examined the stability of the modules with AD progression and with normal aging. We found that in the AD modules, the constituent proteins, interactions and cellular functions were not maintained between consecutive stages through all brain regions. Interestingly, the modules were collapsed with AD progression, specifically in the EC region. By identifying the modules that were affected by AD pathology, we found the transcriptional regulation-associated modules that interact with the proteasome-associated module via UCHL5 hub protein, which is a deubiquitinating enzyme. Considering PINs as a system made of network modules, we found that the modules relevant to the transcriptional regulation are disrupted in the EC region, which affects the ubiquitin-proteasome system.

This study investigated the pathway underlying the antitumor activity of telomelysin, a telomerase-dependent, replication-selective oncolytic adenovirus, in soft tissue sarcoma cells. Treatment with telomelysin alone resulted in simultaneous induction of apoptosis and autophagy, whereas cotreatment with telomelysin and 3-methyladenine significantly reduced cell viability and increased apoptosis and the cellular ATP level compared to treatment with telomelysin alone, indicating that telomelysin-mediated autophagy is a death-protective but not death-promoting process. Cotreatment with Z-Val-Ala-Asp-CH2F significantly increased cellular ATP depletion compared to telomelysin-alone treatment while inhibiting telomelysin-induced apoptosis and having no significant effect on cell viability, indicating that it promotes transition from apoptotic to necrotic cell death., (© 2013 Japanese Cancer Association.)

We studied seven cases of Alzheimer's disease (AD). Six of the patients had presenilin 1 (PS1) mutations (PS1AD). Three novel PS1 mutations (T99A, H131R and L219R) and three other missense mutations (M233L, H163R and V272A) were found in the PS1AD group. We measured the levels of phosphorylated tau (ptau-181, ptau-199) and Aβ (Aβ1-42, Aβ1-40 and Aβ1-38) in the cerebrospinal fluid (CSF) of PS1AD patients, early-onset sporadic AD (EOSAD), late-onset sporadic AD (LOSAD) and non-demented subjects (ND). The CSF levels of Aβ1-42 in the three AD groups were significantly lower than those of the ND group (p < 0.0001). CSF levels of Aβ1-42 in the PS1AD group were significantly lower than those in the two sporadic AD groups. The Aβ1-40 and Aβ1-38 levels in the CSF of the PS1AD group were significantly lower than those of the three other groups (p < 0.0001, respectively). The levels of Aβ1-40, Aβ1-38 and Aβ1-42 in the CSF of the PS1AD group remained lower than those of the ND group for 4 years. Not only CSF Aβ1-42, but also Aβ1-40 and Aβ1-38 decreased in the advanced stages of PS1AD.

Alzheimer's disease (AD) is the most common type of dementia in the elderly and has multiple causes. The amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2) genes were identified as causative genes in a small number of families with autosomal dominant early-onset forms of AD (ADEOAD). However, many AD cases are sporadic and the late-onset type, which develops after 65 years of age. The apolipoprotein gene (APOE) is the strongest risk gene for sporadic and familial late-onset AD (LOAD) regardless of ethnicity. Since about half of the patients with LOAD do not have the risk allele (ε4) of APOE and λs (=5) is larger than λsAPOE (=2.5), risk genes other than APOE are expected to be involved in LOAD. Based on the common disease-common variants hypothesis, genome-wide association studies (GWAS) were performed tenaciously to identify genes related to AD. However, even large-scale GWAS with relatively high frequency of single nucleotide polymorphisms did not reveal any additional risk genes with nearly equal power of APOE. Recently, individual whole genome or whole exon sequencing data obtained using next-generation sequencers have become available. Mutations in the causative genes of ADEOAD have been also observed in both familial LOAD and sporadic EOAD. Furthermore, new causative genes have been identifies in some families by whole genome or exome analyses. Considering the new common disease-rare variants hypothesis, personal genome sequence analysis is a potential strategy for identifying AD risk or protective genes.

SORL1 was shown to be genetically associated with late-onset Alzheimer's disease (LOAD) in a large-scale genome-wide association study (GWAS) involving clinically verified subjects. Here, we attempted to replicate the association of SORL1 in Japanese neuropathologically characterized brain donor subjects (LOAD, 213; control, 370) through a single-nucleotide polymorphism (SNP)-based genetic study involving 19 SNPs: 11 SNPs were selected from the initial study reported by Rogaeva et al. (2007), and the other eight were from our GWAS. Among these SNPs, five exhibited a significant association with LOAD after multiple test correction (p < 2.63E-03 [ = 0.05/19]), which was supported by means of multiple logistic regression analysis with adjustment for age, gender, and carrier status of the APOE ε4 allele. Three of these SNPs (rs985421, rs12364988 [Rogaeva's SNP 7], and rs4598682) were encompassed by a 5' linkage disequilibrium (LD) region, and the remaining two (rs3781834 and rs3781836) by a 3' LD region. Strong LD among SNPs was observed within each LD region, implying that there are two genomic regions showing association with LOAD in SORL1. Case-control haplotype analysis demonstrated that some haplotypes are associated with LOAD in both LD regions. Our replication study strongly supports the preceding evidence that SORL1 is likely one of the genes associated with LOAD.

To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.

Panic disorder (PD) is a moderately heritable anxiety disorder whose pathogenesis is not well understood. Due to the lack of power in previous association studies, genes that are truly associated with PD might not be detected. In this study, we conducted a genome-wide association study (GWAS) in two independent data sets using the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. We obtained imputed genotypes for each GWAS and performed a meta-analysis of two GWAS data sets (718 cases and 1717 controls). For follow-up, 12 single-nucleotide polymorphisms (SNPs) were tested in 329 cases and 861 controls. Gene ontology enrichment and candidate gene analyses were conducted using the GWAS or meta-analysis results. We also applied the polygenic score analysis to our two GWAS samples to test the hypothesis of polygenic components contributing to PD. Although genome-wide significant SNPs were not detected in either of the GWAS nor the meta-analysis, suggestive associations were observed in several loci such as BDKRB2 (P=1.3 × 10(-5), odds ratio=1.31). Among previous candidate genes, supportive evidence for association of NPY5R with PD was obtained (gene-wise corrected P=6.4 × 10(-4)). Polygenic scores calculated from weakly associated SNPs (P<0.3 and 0.4) in the discovery sample were significantly associated with PD status in the target sample in both directions (sample I to sample II and vice versa) (P<0.05). Our findings suggest that large sets of common variants of small effects collectively account for risk of PD.

A variety of 3-substituted benzisoxazoles were reduced with hydrogen using the chiral ruthenium catalyst, {RuCl(p-cymene)[(R,R)-(S,S)-PhTRAP]}Cl. The ruthenium-catalyzed hydrogenation proceeded in high yield in the presence of an acylating agent, affording α-substituted o-hydroxybenzylamines with up to 57% ee. In the catalytic transformation, the N-O bond of the benzisoxazole substrate is reductively cleaved by the ruthenium complex under the hydrogenation conditions. The C-N double bond of the resulting imine is saturated stereoselectively through the PhTRAP-ruthenium catalysis. The hydrogenation produces chiral primary amines, which may work as catalytic poisons, however, the amino group of the hydrogenation product is rapidly acylated when the reaction is conducted in the presence of an appropriate acylating agent, such as Boc₂O or Cbz-OSu.

Background: Alzheimer's disease (AD) is the most common cause of dementia among the elderly. To clarify pathogenesis of AD, thousands of reports have been accumulating. However, knowledge of signaling pathways in the field of AD has not been compiled as a database before., Description: Here, we have constructed a publicly available pathway map called "AlzPathway" that comprehensively catalogs signaling pathways in the field of AD. We have collected and manually curated over 100 review articles related to AD, and have built an AD pathway map using CellDesigner. AlzPathway is currently composed of 1347 molecules and 1070 reactions in neuron, brain blood barrier, presynaptic, postsynaptic, astrocyte, and microglial cells and their cellular localizations. AlzPathway is available as both the SBML (Systems Biology Markup Language) map for CellDesigner and the high resolution image map. AlzPathway is also available as a web service (online map) based on Payao system, a community-based, collaborative web service platform for pathway model curation, enabling continuous updates by AD researchers., Conclusions: AlzPathway is the first comprehensive map of intra, inter and extra cellular AD signaling pathways which can enable mechanistic deciphering of AD pathogenesis. The AlzPathway map is accessible at http://alzpathway.org/.