Gene-gene functional relationships in Alzheimer's disease: CELF1 regulates KLC1 alternative splicing.

The causes of Alzheimer's disease (AD) are poorly understood, although many genes are known to be involved in this pathology. To gain insights into the underlying molecular mechanisms, it is essential to identify the relationships between individual AD genes. Previous work has shown that the splice variant E of KLC1 (KLC1_vE) promotes AD, and that the CELF1 gene, which encodes an RNA-binding protein involved in splicing regulation, is at a risk locus for AD. Here, we identified a functional link between CELF1 and KLC1 in AD pathogenesis. Transcriptomic data from human samples from different ethnic groups revealed that CELF1 mRNA levels are low in AD brains, and the splicing pattern of KLC1 is strongly correlated with CELF1 expression levels. Specifically, KLC1_vE is negatively correlated with CELF1. Depletion and overexpression experiments in cultured cells demonstrated that the CELF1 protein down-regulates KLC1_vE. In a cross-linking and immunoprecipitation sequencing (CLIP-seq) database, CELF1 directly binds to KLC1 RNA, following which it likely modulates terminal exon usage, hence KLC1_vE formation. These findings reveal a new pathogenic pathway where a risk allele of CELF1 is associated with reduced CELF1 expression, which up-regulates KLC1_vE to promote AD.

Characteristics of very late-onset schizophrenia-like psychosis classified with the biomarkers for Alzheimer's disease: a retrospective cross-sectional study.

OBJECTIVES: We aimed to investigate the association between very late-onset schizophrenia-like psychosis (VLOSLP), a schizophrenia spectrum disorder with an onset of ≥60 years, and Alzheimer's disease (AD) using biomarkers. DESIGN: Retrospective cross-sectional study. SETTING: Neuropsychology clinic of Osaka University Hospital in Japan. PARTICIPANTS: Thirty-three participants were classified into three groups: eight AD biomarker-negative VLOSLP (VLOSLP-AD), nine AD biomarker-positive VLOSLP (VLOSLP+AD), and sixteen amnestic mild cognitive impairment due to AD without psychosis (aMCI-P+AD) participants. MEASUREMENTS: Phosphorylated tau levels in the cerebrospinal fluid and 18F-Florbetapir positron emission tomography results were used as AD biomarkers. Several scales (e.g. the Mini-Mental State Examination (MMSE), Wechsler Memory Scale-Revised (WMS-R) Logical Memory (LM) I and II, and Neuropsychiatric Inventory (NPI)-plus) were conducted to assess clinical characteristics. RESULTS: Those in both VLOSLP-AD and +AD groups scored higher than those in aMCI-P+AD in WMS-R LM I. On the other hand, VLOSLP+AD participants scored in between the other two groups in the WMS-R LM II, with only VLOSLP-AD participants scoring significantly higher than aMCI-P+AD participants. There were no significant differences in sex distribution and MMSE scores among the three groups or in the subtype of psychotic symptoms between VLOSLP-AD and +AD participants. Four VLOSLP-AD and five VLOSLP+AD participants harbored partition delusions. Delusion of theft was shown in two VLOSLP-AD patients and five VLOSLP+AD patients. CONCLUSION: Some VLOSLP patients had AD pathology. Clinical characteristics were different between AD biomarker-positive and AD biomarker-negative VLOSLP, which may be helpful for detecting AD pathology in VLOSLP patients.

Models of Aviation Noise Impact in the Context of Operation Decrease at Tan Son Nhat Airport.

Air traffic bans in response to the spread of the coronavirus have changed the sound situation of urban areas around airports. This study aimed to investigate the effect of this unprecedented event on the community response to noise before and after the international flight operation at Tan Son Nhat Airport (TSN) in March 2020. The "before" survey was conducted in August 2019, and the two "after" surveys were conducted in June and September 2020. Structural equation models (SEMs) for noise annoyance and insomnia were developed by linking the questionnaire items of the social surveys. The first effort aimed to achieve a common model of noise annoyance and insomnia, corresponding to the situation before and after the change, respectively. Approximately, 1200 responses were obtained from surveys conducted in 12 residential areas around TSN in 2019 and 2020. The average daily flight numbers observed in August 2019 during the two surveys conducted in 2020 were 728, 413, and 299, respectively. The sound pressure levels of the 12 sites around TSN decreased from 45-81 dB (mean = 64, SD = 9.8) in 2019 to 41-76 dB (mean = 60, SD = 9.8) and 41-73 dB (mean = 59, SD = 9.3) in June and September 2020, respectively. The SEM indicated that the residents' health was related to increased annoyance and insomnia.

Ribavirin Treatment for Severe Schizophrenia with Anti-Borna Disease Virus 1 Antibodies 30 Years after Onset.

Objective: Borna disease virus 1 (BoDV-1) was proven to cause fatal encephalitis in humans in 2018. However, the effects of persistent infections remain unclear. Here, we present the case of a 50-year-old woman with a 30-year history of severe schizophrenia, who was exposed to fleas from stray cats prior to disease onset, suggesting the possibility of zoonosis including BoDV-1 infection. The patient had experienced significant social impairment, thought deterioration, delusions, and hallucinations for more than 20 years. Method: A radioligand assay was used to test the patient for IgG and IgM antibodies against BoDV-1 nucleoprotein (N) and phosphoprotein (P). Based on the protocol for hepatitis C, we treated the patient with 400 mg/day ribavirin, which was later increased to 600 mg/day. Results: The serological examination revealed anti-BoDV-1 N IgG. Although only subtle changes were observed over the 24 weeks of treatment, the family noticed that the patient's Cotard delusions had disappeared 7 months after completing the treatment, accompanied by some improvements in the relationship with the family. Conclusion: Though definite proof was not obtained, this presumed suppression of BoDV-1 by ribavirin leading to improvements in Cotard syndrome-like symptoms suggests that intractable schizophrenia might be one of the BoDV-1 infection phenotypes. Further studies are needed to clarify the effect of persistent BoDV-1 infections in humans.

Representative Exposure-Annoyance Relationships Due to Transportation Noises in Japan.

This paper focuses on clarifying the relationship between noise exposure and the prevalence of highly annoyed people due to transportation noise in Japan. The authors accumulated 34 datasets, which were provided by Socio-Acoustic Survey Data Archive and derived from the other surveys conducted in Japan. All the datasets include the following micro-data: demographic factors, exposure, and annoyance data associated with specific noise sources. We performed secondary analyses using micro-data and established the relationships between noise exposure (Lden) and the percentage of highly annoyed people (%HA) for the following noise source: road traffic, conventional railway, Shinkansen railway, civil aircraft, and military aircraft noises. Among the five transportation noises, %HA for the military aircraft noise is the highest, followed by civil aircraft noise and Shinkansen railway noise. The %HA for conventional railway noise was higher than that for road traffic noise. To validate the representativeness of the exposure-response curves, we have discussed factors affecting the difference in annoyance. In addition, comparing the Japanese relationship with that shown in the "Environmental Noise Guidelines for the European Region," we revealed that Japanese annoyance is higher than the WHO-reported annoyance.

Case Report: Usefulness of Biomarkers for Alzheimer's Disease in Two Cases With Very-Late-Onset Schizophrenia-Like Psychosis.

The association between primary psychotic disorders emerging in later life and neurodegenerative diseases, including Alzheimer's disease (AD), is controversial. We present two female non-demented cases of psychosis with onset above the age of 60 years. Cases 1 and 2 were aged was 68 and 81 years, respectively. They suffered from persecutory delusions and scored 28 on the Mini-Mental State Examination (MMSE) at the first examination. Although detailed neuropsychological tests detected amnesia, they had preserved daily life function. Brain magnetic resonance imaging, N-isopropyl-p-[123I] iodoamphetamine (123I-IMP) single-photon emission computed tomography, and cardiac [123I]-metaiodobenzylguanidine (123I-MIBG) scintigraphy showed no specific abnormalities in either case. We diagnosed them with very-late-onset schizophrenia-like psychosis (VLOSLP) because there was no evidence that their psychoses were derived from organic diseases or affective disorders. Upon close inspection, the AD biomarkers, cerebrospinal fluid (CSF) testing and Florbetapir F 18 positron emission tomography (PET), were positive in Case 1 and negative in Case 2. Case 1 scored 25 1 year later and 23 2 years later on the MMSE and was finally diagnosed as AD dementia. These two cases suggest that some clinically diagnosed VLOSLPs may be a prodromal AD. Although VLOSLP is a disease entity supposed to be a primary psychotic disorder, some are probably secondary psychosis with insidious neurodegeneration. Advanced biomarkers such as amyloid PET and CSF may contribute to the detection of secondary psychosis from clinically diagnosed VLOSLP.

Effects of Noise and Vibration Due to the Hokuriku Shinkansen Railway on the Living Environment: A Socio-Acoustic Survey One Year after the Opening.

One year after the opening of the Hokuriku Shinkansen (high-speed) railway, in 2016, we conducted a social survey targeting the residents of detached houses along the rail. Noise and vibration exposure levels were estimated at outdoor points closest to the noise source side of the houses. Of the 1980 people contacted, there were 1022 valid respondents. The purpose of this research was to investigate the relationship between noise and vibration exposure and community responses. The results demonstrated that the noise annoyance and daily activity disturbances of residents living in areas without a conventional railway are higher than those of residents living in areas running parallel to a conventional railway line. This tendency was remarkable, especially for areas with high vibration exposure caused by the Shinkansen railway. There was no difference between before and after the opening of the Shinkansen railway in the evaluation of housing satisfaction, or regarding the preference for the residential area and quietness around the house. However, since the survey before the opening was conducted only in the Ishikawa site, it will be necessary to conduct before-and-after surveys in areas where there are no conventional railways, and where the speed of the Shinkansen is fast.

The Effect of an Alternative Definition of "Percent Highly Annoyed" on the Exposure-Response Relationship: Comparison of Noise Annoyance Responses Measured by ICBEN 5-Point Verbal and 11-Point Numerical Scales.

Since the development of the 5-point verbal and 11-point numerical scales for measuring noise annoyance by the ICBEN Team 6, these scales have been widely used in socio-acoustic surveys worldwide, and annoyance responses have been easily compared internationally. However, both the top two categories of the 5-point verbal scale and the top three ones of the 11-point numerical scale are correspond to high annoyance, so it is difficult to precisely compare annoyance responses. Therefore, we calculated differences in day-evening-night-weighted sound pressure levels (Lden) by comparing values corresponding to 10% highly annoyed (HA) on Lden_%HA curves obtained from measurements in 40 datasets regarding surveys conducted in Japan and Vietnam. The results showed that the Lden value corresponding to 10% HA using the 5-point verbal scale was approximately 5 dB lower than that of the 11-point numerical scale. Thus, some correction is required to compare annoyance responses measured by the 5-point verbal and the 11-point numerical scales. The results of this study were also compared with those of a survey in Switzerland.

How Does a Community Respond to Changes in Aircraft Noise? A Comparison of Two Surveys Conducted 11 Years Apart in Ho Chi Minh City.

There have been many arguments about findings of an increase in noise annoyance over time and a recommendation of stricter limits on aircraft noise levels to protect the health of residents around airports. It is crucial to examine if the established exposure-response relationship is suitable for designing future aircraft noise regulations. This study was focused on identifying changes in response to noise over time by comparing community responses from two surveys conducted in 2008 and 2019 at Tân SÆ¡n Nhat (TSN) international airport. Annoyance was found to significantly reduce in 2019 compared to 2008; however, changes in sleep quality were relatively small. Unexpectedly, a gradual increase in the annoyance due to aircraft noise was not found. Results of multiple regression analysis indicated that differences in the reaction of the residents to noise in the two studies were significantly attributed to nonacoustic factors. Noise sensitivity and dissatisfaction with the living environment (e.g., inconvenience in accessing workplace) considerably affect noise annoyance, whereas noise sensitivity, age, and dissatisfaction with the green environment of living areas affect sleep quality. These findings suggest the fulfillment of desired living environment as effective measures for mitigating noise impacts on residents in the vicinity of busy airports.

Effects of Changes in Acoustic and Non-Acoustic Factors on Public Health and Reactions: Follow-Up Surveys in the Vicinity of the Hanoi Noi Bai International Airport.

Herein, the effects of changes in acoustic and non-acoustic factors on public health and reactions were assessed using two follow-up investigations; this was achieved after three surveys were conducted on the impact of the step change in noise caused by the increased number of flights at the Noi Bai International Airport in Hanoi (Vietnam) after the new terminal building was opened to the public. Exposure-response relationships established in the follow-up studies were less in number than those established in 2015 after the step change had occurred, and were almost similar to the relationship established in the survey conducted before the step change; however, these relationships were significantly greater than those established in the European Union position paper. Comparisons between respondents with high blood pressure and insomnia ratios at different noise level ranges showed that there is no significant association between ratios of high blood pressure and day-evening-night noise levels; however, an exposure-response relationship was discovered between insomnia and night-time noise levels. Non-acoustic factors such as noise sensitivity, sound insulation capacity of houses, and length of residence were found to curb the respondents' annoyance, insomnia, and high blood pressure. Thus, an improvement in residence quality and a restriction on nighttime flight operation is necessitated.

Biology of splicing in Alzheimer's disease research.

Alzheimer's disease (AD) is the most common neurodegenerative disease, leading to dementia in the aging human brain. Although a huge amount of research has been done to date, the pathogenesis of AD remains largely unknown. Given the dominance of mRNA splicing in the nervous system, it would be invaluable to precisely identify mis-splicing in the AD brain to understand more deeply how the gene network orchestrates the development of pathology in affected cells. In this brief manuscript, we first introduce the term mRNA splicing and discuss its abnormality in the AD brain. Then, we describe the technical challenges of the precise detection of mis-splicing, as well as their reasonable solutions. Finally, we discuss the future directions for splicing biology in AD.

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-ß accumulation in Alzheimer's disease.

Alzheimer's disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-ß (Aß) in human brain is still not well understood. To identify novel genes that cause accumulation of Aß in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aß level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aß accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.

Combined Effects of High-Speed Railway Noise and Ground Vibrations on Annoyance.

The Shinkansen super-express railway system in Japan has greatly increased its capacity and has expanded nationwide. However, many inhabitants in areas along the railways have been disturbed by noise and ground vibration from the trains. Additionally, the Shinkansen railway emits a higher level of ground vibration than conventional railways at the same noise level. These findings imply that building vibrations affect living environments as significantly as the associated noise. Therefore, it is imperative to quantify the effects of noise and vibration exposures on each annoyance under simultaneous exposure. We performed a secondary analysis using individual datasets of exposure and community response associated with Shinkansen railway noise and vibration. The data consisted of six socio-acoustic surveys, which were conducted separately over the last 20 years in Japan. Applying a logistic regression analysis to the datasets, we confirmed the combined effects of vibration/noise exposure on noise/vibration annoyance. Moreover, we proposed a representative relationship between noise and vibration exposures, and the prevalence of each annoyance associated with the Shinkansen railway.

A genome-wide association study of late-onset Alzheimer's disease in a Japanese population.

OBJECTIVE: Although a number of genome-wide association studies (GWASs) of late-onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations. DESIGN: To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-ε4 status to eliminate the established effect of APOE region. RESULTS: Our data indicated that 18p11.32 (rs1992269, P = 9.77 × 10(-7)), CNTNAP2 (rs802571, P = 1.26 × 10(-6)), and 12q24.23 (rs11613092, P = 6.85 × 10(-6)) were suggestive loci for susceptibility to LOAD. CONCLUSION: We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective.

Atlas stumbled: kinesin light chain-1 variant E triggers a vicious cycle of axonal transport disruption and amyloid-ß generation in Alzheimer's disease.

Substantial evidence implicates fast axonal transport (FAT) defects in neurodegeneration. In Alzheimer's disease (AD), it is controversial whether transport defects cause or arise from amyloid-ß (Aß)-induced toxicity. Using a novel, unbiased genetic screen, Morihara et al. identified kinesin light chain-1 splice variant E (KLC1vE) as a modifier of Aß accumulation. Here, we propose three mechanisms to explain this causal role. First, KLC1vE reduces APP transport, leading to Aß accumulation. Second, reduced transport of APP by KLC1vE triggers an ER stress response that activates the amyloidogenic pathway. Third, KLC1vE impairs transport of other KLC1 cargos that regulate amyloidogenesis, promoting Aß retention within the secretory pathway. Collectively, KLC1vE perpetuates a vicious cycle of Aß generation, kinase dysregulation, and global FAT impairment that inevitably leads to cellular toxicity. These concepts implicate alternative splicing of KLC1 in AD and suggest that the reciprocal influence of transport mechanisms on disease states contributes to neurodegeneration.

Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population.

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.

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-ß accumulation modifier.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of Aß accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aß accumulation. To avoid detecting secondarily affected genes by Aß, we used non-Tg mice in the absence of Aß pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an Aß modifier, indicating a role for intracellular trafficking in Aß accumulation. Aß levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of Aß, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aß pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases.

SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians.

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.

The AKT1 gene is associated with attention and brain morphology in schizophrenia.

OBJECTIVES: A meta-analysis of the associations between genetic variants in the AKT1 gene and schizophrenia found that a single nucleotide polymorphism (SNP5; rs2494732) was associated with schizophrenia in Asian populations. METHODS: In this study, we investigated the effects of this SNP on memory and attentional performance and brain structure using magnetic resonance imaging in a Japanese population (117 patients with schizophrenia and 189 healthy subjects). RESULTS: The memory performance, particularly attention/concentration score, measured by the Wechsler Memory Scale-Revised in A carriers of SNP5, which was found to be enriched in patients with schizophrenia, was lower than that in individuals with the G/G genotype. We confirmed the association of the SNP with attentional performance using the Continuous Performance Test, which assessed sustained attention and vigilance of attentional function. Patients with A allele demonstrated lower attentional performance than patients with the G/G genotype. Patients with the A allele had smaller gray matter volumes in the right inferior parietal lobule related to attentional processes and in the frontostriatal region related to different SNPs in AKT1 than patients with the G/G genotype. CONCLUSIONS: Our results suggest that a genetic variant of AKT1 might be associated with attentional deficits and brain morphological vulnerability in patients with schizophrenia.