Insulin regulates Presenilin 1 localization via PI3K/Akt signaling.

Recently, insulin signaling has been highlighted in the pathology of Alzheimer's disease (AD). Although the association between insulin signaling and Tau pathology has been investigated in several studies, the interaction between insulin signaling and Presenilin 1 (PS1), a key molecule of amyloid beta (Abeta) pathology, has not been elucidated so far. In this study, we demonstrated that insulin inhibited PS1 phosphorylation at serine residues (serine 353, 357) via phosphatidylinositol 3-kinase (PI3K)/Akt signal pathway and strengthened the trimeric complex of PS1/N-cadherin/beta-catenin, consequently relocalizing PS1 to the cell surface. Since our recent report suggests that PS1/N-cadherin/beta-catenin complex regulates Abeta production, it is likely that insulin signaling affects Abeta pathology by regulating PS1 localization

Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer’s disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair. Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy

Acute inhibition of AMPA receptors by perampanel reduces amyloid β-protein levels by suppressing β-cleavage of APP in Alzheimer's disease models

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aβ deposition in AD since enhanced neuronal activity promotes presynaptic Aβ production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aβ-evoked neuronal hyperexcitability, the acute effects of PER on Aβ metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aβ40 and Aβ42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aβ40 /Aβ42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP βCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPβ levels, a direct byproduct of β-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aβ-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aβ clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aβ, indicating that the acute effect of PER is predominantly on Aβ production. In conclusion, acute treatment of PER reduces Aβ production by suppressing β-cleavage of amyloid-β precursor protein effectively, indicating a potential effect of PER against Aβ pathology in AD

The modeling of Alzheimer's disease by the overexpression of mutant Presenilin 1 in human embryonic stem cells.

Cellular disease models are useful tools for Alzheimer's disease (AD) research. Pluripotent stem cells, including human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), are promising materials for creating cellular models of such diseases. In the present study, we established cellular models of AD in hESCs that overexpressed the mutant Presenilin 1 (PS1) gene with the use of a site-specific gene integration system. The overexpression of PS1 did not affect the undifferentiated status or the neural differentiation ability of the hESCs. We found increases in the ratios of amyloid-β 42 (Aβ42)/Aβ40 and Aβ43/Aβ40. Furthermore, synaptic dysfunction was observed in a cellular model of AD that overexpressed mutant PS1. These results suggest that the AD phenotypes, in particular, the electrophysiological abnormality of the synapses in our AD models might be useful for AD research and drug discovery

Reminiscence therapy using virtual reality technology affects cognitive function and subjective well-being in older adults with dementia

Reminiscence therapy is garnering attention for stimulating seniors’ cognitive functions. It could be inferred that that synergistic effects could be created by combining virtual reality (VR), which can project realistic images, with recall, which stimulates memory. We hypothesized that by projecting realistic memories to stimulate recall, VR-based reminiscence therapy would stimulate cognitive function better than conventional photo-based reminiscence therapy. We randomly assigned total 52 people with mild cognitive impairment to eight weeks of reminiscence therapy using either tablet VR panoramas or conventional still photos with 26 participants in each group. Before and after therapy, we tested their cognitive functions with the mini-mental state examination (MMSE), the revised PGC morale scale, multidimensional observation scale for elderly subjects, trail making tests A and B, and the word fluency test. The total scores of MMSE showed improvement for both groups, but did not show statistical significance of the VR panoramas group over the conventional still photos group. However, of the two groups, only the VR panoramas group showed considerable improvement from the baseline. In addition, the analysis of secondary outcome showed that the revised PGC morale scale scores rose considerably higher in the VR panoramas group than in the still photos group. No definite differences were observed in other scales. Contrary to our primary hypothesis, reminiscence therapy produced cognitive improvement regardless of whether its stimuli were still photos or VR panoramas. However, the greater improvement in VR participants’ revised PGC morale scale scores shows enhancement of patients’ subjective well-being

Videophone-based multimodal home telecare support system for patients with diabetes

[Aims]We conducted an intervention study to clarify how effectively a telemedicine system using a multi-functional videophone could be used in lifestyle guidance, with special focus on diet for diabetic patients cared for at home. [Methods]Patients were assigned to a 3-month intervention group or to a usual care group. In the intervention group, patients and a medical professional communicated bi-directionally through a videophone-based communication system for 30 min, once a week. The participants were encouraged to send pictures of each meal online, through the videophone system, in real time. [Results]In intra-subjective comparison, the 3-month intervention program resulted in a significant decrease in body weight (BW) (p < 0.0005) and average HbA1C level (p < 0.005) compared with before the intervention program. Three months after the conclusion of the intervention program, average HbA1C levels returned to almost the same levels as before intervention (p < 0.05). In the usual care group, average HbA1C level did not change significantly for 6 months. [Conclusions]3-month intensive communication using the multimodal videophone system led to a significant decrease in BW and average HbA1C level. This novel bi-directional communication is useful for improving conditions such as diabetes, BW, and hyperglycemia for homecare diabetes patients, thus, reducing cardiovascular risk

The relationship between hospital ethical climate and continuing education in nursing ethics.

BackgroundIn recent years, there has been a growing interest in the importance of creating a healthy ethical climate. Although relationship with various factors and the ethical climate have been reported, understanding of the relationship between ethical education and ethical climate is limited.AimThis study aims to investigate the relationship between ethical climate, personal characteristics, and continuing education for ethics.MethodsThis study conducted a quantitative cross-sectional survey of 605 nurses in 3 teaching hospitals in Japan. Multiple-regression analysis was used to assess the relationship between ethical climate and demographic characteristics and continuing education. Further mean of ethical climate scores were compared between received continuing education and did not, using analysis of covariance adjusted for demographic variables.FindingsThe ethical climate showed significant association with hospital, gender, specialty of the unit, experience of ethics education, in-service ethical training, and workshops/ academic conferences on nursing ethics. In multiple-regression analysis, attending in-service ethical training increased the mean of ethical climate score (p = 0.031) and workshops/ academic conferences decreased the mean score (p = 0.028). Adjusted-mean of ethical climate score of nurses who had in-service training was significantly higher than those who had not (p = 0.038), whereas adjusted-mean of it of nurses who had attended workshops/ academic conferences was significant lower (p = 0.033).DiscussionIn-service training on ethics was associated with the positive ethical climate. Hospital should enhance ethical education.ConclusionEthical climate related to the nurses' personal characteristics and continuing education. We propose that organizational support for ethical education may be effective in raising the ethical climate of the workplace

Vocabulary Size in Speech May Be an Early Indicator of Cognitive Impairment.

Little is known about the relationship between mild cognitive impairment (MCI) and changes to language abilities. Here, we used the revised Hasegawa Dementia Scale (HDS-R) to identify suspected MCI in elderly individuals. We then analyzed written and spoken narratives to compare the language abilities between study participants with and without MCI in order to explore the relationship between cognitive and language abilities, and to identify a possible indicator for the early detection of MCI and dementia. We recruited 22 people aged 74 to 86 years (mean: 78.32 years; standard deviation: 3.36). The participants were requested to write and talk about one of the happiest events in their lives. Based on HDS-R scores, we divided the participants into 2 groups: the MCI Group comprised 8 participants with a score of 26 or lower, while the Healthy Group comprised 14 participants with a score of 27 or higher. The transcriptions of both written and spoken samples for each participant were used in the measurement of NLP-based language ability scores. Our analysis showed no significant differences in writing abilities between the 2 groups in any of the language ability scores. However, analysis of the spoken narrative showed that the MCI Group had a significantly larger vocabulary size. In addition, analysis of a metric that signified the gap in content between the spoken and written narratives also revealed a larger vocabulary size in the MCI Group. Individuals with early-stage MCI may be engaging in behavior to conceal their deteriorating cognition, thereby leading to a temporary increase in their active spoken vocabulary. These results indicate the possible detection of early stages of reduced cognition before dementia onset through the analysis of spoken narratives

The participation of insulin-like growth factor-binding protein 3 released by astrocytes in the pathology of Alzheimer's disease.

[Background]Alzheimer’s disease (AD) is characterized by senile plaques, extracellular deposits composed primarily of amyloid–beta (Aβ), and neurofibrillary tangles, which are abnormal intracellular inclusions containing hyperphosphorylated tau. The amyloid cascade hypothesis posits that the deposition of Aβ in the brain parenchyma initiates a sequence of events that leads to dementia. However, the molecular process by which the extracellular accumulation of Aβ peptides promotes intracellular pathologic changes in tau filaments remains unclear. To elucidate this process, we presumed that astrocytes might trigger neuronal reactions, leading to tau phosphorylation. In this study, we examined AD pathology from the perspective of the astrocyte-neuron interaction. [Results]A cytokine-array analysis revealed that Aβ stimulates astrocytes to release several chemical mediators that are primarily related to inflammation and cell adhesion. Among those mediators, insulin-like growth factor (IGF)-binding protein 3 (IGFBP-3) was highly upregulated. In AD brains, the expression of IGFBP-3 was found to be increased by western blot analysis, and increased expression of IGFBP-3 was observed in astrocytes via fluorescence microscopy. In addition, we reproduced the increase in IGFBP-3 after treatment with Aβ using human astrocytoma cell lines and found that IGFBP-3 was expressed via calcineurin. In AD brains, the activated forms of calcineurin were found to be increased by western blot analysis, and increased expression of calcineurin was observed in astrocytes via fluorescence microscopy. When Ser9 of glycogen synthase kinase-3β (GSK-3β) is phosphorylated, GSK-3β is controlled and tau phosphorylation is suppressed. Aβ suppresses the phosphorylation of GSK-3β, leading to tau phosphorylation. In this study, we found that IGF-Ι suppressed tau phosphorylation induced by Aβ, although IGFBP-3 inhibited this property of IGF-Ι. As a result, IGFBP-3 contributed to tau phosphorylation and cell death induced by Aβ. [Conclusions]Our study suggested that calcineurin in astrocytes was activated by Aβ, leading to IGFBP-3 release. We further demonstrated that IGFBP-3 produced by astrocytes induced tau phosphorylation in neurons. Our study provides novel insights into the role of astrocytes in the induction of tau phosphorylation and suggests that IGFBP-3 could be an important link between Aβ and tau pathology and an important therapeutic target

Factors associated with the job satisfaction of certified nurses and nurse specialists in cancer care in Japan: Analysis based on the Basic Plan to Promote Cancer Control Programs.

BACKGROUND:As the Japanese population ages, the number of cancer patients will likely increase. Therefore, qualified cancer health care providers should be recruited and retained. Nurse job satisfaction is influenced by numerous factors and may affect staff turnover and patient outcomes. OBJECTIVES:To evaluate the job satisfaction of certified nurses and nurse specialists in Japanese cancer care and elucidate factors associated with job satisfaction. METHODS:Participants in this cross-sectional study comprised 200 certified nurse specialists and 1,472 certified nurses working in Japanese cancer care. A chi-square test and logistic regression analysis were conducted to identify job satisfaction factors. RESULTS:Job satisfaction was present in 38.45% and 49.00% of certified nurses and nurse specialists, respectively. Certified nurses associated job satisfaction with cross-departmental activities (OR 2.24, p<0.001), positive evaluation from senior stuff (OR 4.58, p<0.001), appropriate staff allocation (OR 1.75, p<0.001), more than five years certified nurse experience (OR 1.91, p<0.001), and positive evaluation of the development of certified nurses (OR 2.13, p<0.01) and nurse specialists (OR 1.37, p<0.05). Low job satisfaction was associated with working on a ward (OR 0.51, p<0.001) and a capacity of more than 200 beds (OR 0.33, p = 0.00). Certified nurse specialists associated job satisfaction with palliative care team participation (OR 2.64, p<0.05), cross-sectional activities (OR 7.06, p<0.01), positive evaluation from senior stuff (OR 13.15, p<0.001), presence of certified nurses in radiation therapy (OR 2.91, p<0.05), positive certified nurse specialist development evaluation (OR 7.35, p<0.001), medical service fees (OR 3.78, p<0.01), and independent activities (OR 11.34, p<0.01). CONCLUSIONS:We identified factors related to activities, facilities, and the cancer care team associated with job satisfaction of certified nurses and nurse specialists in Japanese cancer care. Suggestions are provided to enhance job satisfaction through Japan's Basic Plan to Promote Cancer Control, which may help hospital administrators retain nursing staff