Worldwide, Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid ...β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, Aβ molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these Aβ species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of Aβ and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent studies using synthetic Aβ peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of Aβ, particularly Aβ protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of Aβ
disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms.
Dietary fibers are metabolized by gastrointestinal (GI) bacteria into short-chain fatty acids (SCFAs). We investigated the potential role of these SCFAs in β-amyloid (Aβ) mediated pathological ...processes that play key roles in Alzheimer's disease (AD) pathogenesis.
Multiple complementary assays were used to investigate individual SCFAs for their dose-responsive effects in interfering with the assembly of Aβß1-40 and Aβ1-42 peptides into soluble neurotoxic Aβ aggregates.
We found that several select SCFAs are capable of potently inhibiting Aβ aggregations, in vitro.
Our studies support the hypothesis that intestinal microbiota may help protect against AD, in part, by supporting the generation of select SCFAs, which interfere with the formation of toxic soluble Aβ aggregates.
The ever-changing social implications of the COVID-19 pandemic have resulted in an urgent need to understand the working environments and health status of workers. We conducted a nationwide ...Internet-based health survey of Japanese workers in December 2020, in the midst the country’s “third wave” of COVID-19 infection. Of 33,087 surveys collected, 6,051 were determined to have invalid responses. The 27,036 surveys included in the study were balanced in terms of geographical area, sex of participants, and type of work, according to the sampling plan. Men were more likely than women to have telecommuted, while women were more likely to have resigned since April 2020. Forty percent and 9.1% of respondents had a K6 score of 5 or higher and 13 or higher, respectively, and they did not exhibit extremely poor health. The present study describes the protocol used to conduct an Internet-based health survey of workers and a summary of its results during a period when COVID-19 was spreading rapidly in Japan. In the future, we plan to use this survey to examine the impact of COVID-19 on workersʼ work styles and health.
Alzheimer's disease (AD), a slow progressive form of dementia, is clinically characterized by cognitive dysfunction and memory impairment and neuropathologically characterized by the accumulation of ...extracellular plaques containing amyloid β-protein (Aβ) and neurofibrillary tangles containing tau in the brain, with neuronal degeneration and high level of oxidative stress. The current treatments for AD, e.g., acetylcholinesterase inhibitors (AChEIs), have efficacies limited to symptom improvement. Although there are various approaches to the disease modifying therapies of AD, none of them can be used alone for actual treatment, and combination therapy may be needed for amelioration of the progression. There are reports that cilostazol (CSZ) suppressed cognitive decline progression in patients with mild cognitive impairment or stable AD receiving AChEIs. Previously, we showed that CSZ suppressed Aβ-induced neurotoxicity in SH-SY5Y cells
coincident inhibition of oxidative stress, as demonstrated by reduced activity of nicotinamide adenine dinucleotide phosphate oxidase, accumulation of reactive oxygen species, and signaling of mitogen-activated protein kinase. CSZ also rescued cognitive impairment and promoted soluble Aβ clearance in a mouse model of cerebral amyloid angiopathy. Mature Aβ fibrils have long been considered the primary neurodegenerative factors in AD; however, recent evidence indicates soluble oligomers to initiate the neuronal and synaptic dysfunction related to AD and other protein-misfolding diseases. Further underscoring the potential of CSZ for AD treatment, we recently described the inhibitory effects of CSZ on Aβ oligomerization and aggregation
. In this review, we discuss the possibility of CSZ as a potential disease-modifying therapy for the prevention or delay of AD.
Excessive accumulation of amyloid β-protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer's disease (AD). Protofibrils, ...one of the high-molecular-weight Aβ oligomers (HMW-Aβo), are implicated to be important targets of disease modifying therapy of AD.
We previously reported that phenolic compounds such as myricetin inhibit Aβ1-40, Aβ1-42, and α-synuclein aggregations, including their oligomerizations, which may exert protective effects against AD and Parkinson's disease. The purpose of this study was to clarify the detailed mechanism of the protective effect of myricetin against the neurotoxicity of HMW-Aβo in SH-SY5Y cells.
To assess the effect of myricetin on HMW-Aβo-induced oxidative stress, we systematically examined the level of membrane oxidative damage by measuring cell membrane lipid peroxidation, membrane fluidity, and cell membrane potential, and the mitochondrial oxidative damage was evaluated by mitochondrial permeability transition (MPT), mitochondrial reactive oxygen species (ROS), and manganese-superoxide dismutase (Mn-SOD), and adenosine triphosphate (ATP) assay in SH-SY5Y cells.
Myricetin has been found to increased cell viability by suppression of HMW-Aβo-induced membrane disruption in SH-SY5Y cells, as shown in reducing membrane phospholipid peroxidation and increasing membrane fluidity and membrane resistance. Myricetin has also been found to suppress HMW-Aβo-induced mitochondria dysfunction, as demonstrated in decreasing MPT, Mn-SOD, and ATP generation, raising mitochondrial membrane potential, and increasing mitochondrial-ROS generation.
These results suggest that myricetin preventing HMW-Aβo-induced neurotoxicity through multiple antioxidant functions may be developed as a disease-modifying agent against AD.
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•Myricetin suppresses neurotoxicity by high molecular weight amyloid β oligomers.•The therapeutic target is oxidative stress at the cell membrane and mitochondria.•It not only works as an antioxidant but boosts the antioxidant function of neurons.•Myricetin may be developed as a disease-modifying agent for Alzheimer's disease.
To prevent the spread of infection, it is necessary for each individual to adopt infection prevention behavior. We investigated the effect of infection control measures implemented in the workplace ...on personal infection prevention behavior. We conducted a self-administered questionnaire survey through the Internet from December 22 to 25, 2020, during which period coronavirus disease 2019 (COVID-19) was spreading. Among respondents aged 20 to 65 years (n=27,036), 21,915 workers were included in the analysis. The results showed that as the number of infection control measures in the workplace increased, implementation of infection prevention behavior by individuals also significantly increased. However, the relationship differed depending on the type of personal infection prevention behavior. Specifically, infection control measures against COVID-19 in the workplace may affect personal infection prevention behavior. Implementation of infection control measures in the workplace increases awareness of the importance of individual infection prevention behavior and its implementation by all individuals. These findings may be applicable not only to COVID-19 measures but also to responses to other emerging infections and seasonal influenza.
The present study examined the relationship between the intensity of home-based telework and work engagement.
This cross-sectional study using a self-administrated questionnaire survey was conducted ...from December 22 to 25, 2020, in Japan. The subjects were asked single-item questions about the intensity of telework and three-item questions about work engagement using the Utrecht Work Engagement Scale. Coefficients were estimated using a multilevel regression model nested by the prefecture of residence and adjusted for covariates.
High-intensity (4 or more days per week) telework was not associated with high work engagement for men or women. In contrast, low and moderate intensity (3 days per week to once per month) were associated with high work engagement. The results were consistent when stratified by sex.
Reasonable-intensity telework may have beneficial effects on work engagement.
We examined the association between socioeconomic and health status, and lifestyle and sickness presenteeism among Japanese workers during the COVID-19 epidemic.
A cross-sectional study using an ...Internet-monitor survey was conducted in December, 2020 in Japan. Of 33,302 survey participants, we analyzed 27,036 participants (13,814 men and 13,222 women) who reported experience with sickness presenteeism.
The odds ratio (OR) of sickness presenteeism associated with unmarried versus married status was 1.15. Respective figures for other variables were 1.11 for manual laboring work compared to desk work; 1.79 and 2.29 for loss of employment at the time the pandemic began and continuation of unemployment compared with maintaining employment during the pandemic; and 3.34 for a feeling of financial instability compared with stability.
The issue of sickness presenteeism has become more prominent under the COVID-19 epidemic.
Globally, residents of long-term care facilities (LTCFs) often experience adverse events (AEs) and corresponding lawsuits that result in suffering among the residents, their families, and the ...facilities. Hence, we conducted a study to clarify the factors related to the facilities' liabilities for damages for the AEs that occur at LTCFs in Japan. We analyzed 1,495 AE reports from LTCFs in one Japanese city. A binomial logistic regression analysis was conducted to identify factors associated with liability for damages. The independent variables were classified as: residents, organizations, and social factors. In total, 14% of AEs resulted in the facility being liable for damages. The predictors of liability for damages were as follows: for the resident factors, the increased need for care had an adjusted odds ratio (AOR) of 2.00 and care levels of 2-3; and AOR of 2.48 and care levels of 4-5. The types of injuries, such as bruises, wounds, and fractures, had AORs of 3.16, 2.62, and 2.50, respectively. Regarding the organization factors, the AE time, such as noon or evening, had an AOR of 1.85. If the AE occurred indoors, the AOR was 2.78, and if it occurred during staff care, the AOR was 2.11. For any follow-ups requiring consultation with a doctor, the AOR was 4.70, and for hospitalization, the AOR was 1.76. Regarding the type of LTCF providing medical care in addition to residential care, the AOR was 4.39. Regarding the social factors, the reports filed before 2017 had an AOR of 0.58. The results of the organization factors suggest that liability tends to arise in situations where the residents and their family expect high quality care. Therefore, it is imperative to strengthen organizational factors in such situations to avoid AEs and the resulting liability for damages.
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