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Aim: Aggravated neuronal loss, caused mainly by neuronal apoptosis, is observed in the brain of patients with Alzheimer's disease (AD) and animal models of AD. A truncated form of Dual‐specific and tyrosine phosphorylation‐regulated protein kinase 1A (Dyrk1A) plays a vital role in AD pathogenesis. Downregulation of anti‐apoptotic Bcl‐xL is tightly correlated with neuronal loss in AD. However, the molecular regulation of neuronal apoptosis and Bcl‐x expression by Dyrk1A in AD remains largely elusive. Here, we aimed to explore the role and molecular mechanism of Dyrk1A in apoptosis. Methods: Cell Counting Kit‐8 (CCK8), flow cytometry, and TdT‐mediated dUTP Nick‐End Labeling (TUNEL) were used to check apoptosis. The cells, transfected with Dyrk1A or/and ASF with Bcl‐x minigene, were used to assay Bcl‐x expression by RT‐PCR and Western blots. Co‐immunoprecipitation, autoradiography, and immunofluorescence were conducted to check the interaction of ASF and Dyrk1A. Gene set enrichment analysis (GSEA) of apoptosis‐related genes was performed in mice overexpressing Dyrk1A (TgDyrk1A) and AD model 5xFAD mice. Results: Dyrk1A promoted Bcl‐xS expression and apoptosis. Splicing factor ASF promoted Bcl‐x exon 2b inclusion, leading to increased Bcl‐xL expression. Dyrk1A suppressed ASF‐mediated Bcl‐x exon 2b inclusion via phosphorylation. The C‐terminus deletion of Dyrk1A facilitated its binding and kinase activity to ASF. Moreover, Dyrk1a1–483 further suppressed the ASF‐mediated Bcl‐x exon 2b inclusion and aggravated apoptosis. The truncated Dyrk1A, increased Bcl‐xS, and enrichment of apoptosis‐related genes was observed in the brain of 5xFAD mice. Conclusions: We speculate that increased Dyrk1A and truncated Dyrk1A may aggravate neuronal apoptosis by decreasing the ratio of Bcl‐xL/Bcl‐xS via phosphorylating ASF in AD. [ABSTRACT FROM AUTHOR]

Tauopathies are a group of neurodegenerative diseases whose central feature is dysfunction of the microtubule-associated protein tau (MAPT). Although the exact etiology of tauopathies is still unknown, it has been hypothesized that their onset may occur up to twenty years before the clear emergence of symptoms, which has led to questions about whether the prognosis of these diseases can be improved by, for instance, targeting the factors that influence tauopathy development. One such factor is hypoxia, which is strongly linked to Alzheimer's disease because of its association with obstructive sleep apnea and has been reported to affect molecular pathways related to the dysfunction and aggregation of tau proteins and other biomarkers of neurological damage. In particular, hypobaric hypoxia exposure increases the activation of several kinases related to the hyperphosphorylation of tau in neuronal cells, such as ERK, GSK3β, and CDK5. In addition, hypoxia also increases the levels of inflammatory molecules (IL-β1, IL-6, and TNF-α), which are also associated with neurodegeneration. This review discusses the many remaining questions regarding the influence of hypoxia on tauopathies and the contribution of high-altitude exposure to the development of these diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD), the most common cause of dementia and the fifth leading cause of death in the adult population has a complex pathophysiological link with hypertension (HTN). A growing volume of published literature on a parallel elevation of blood pressure (BP), amyloid plaques, and neurofibrillary tangles formation in post-middle of human brain cells has developed new, widely accepting foundations on this association. In particular, HTN in elderly life mediates cerebral blood flow dysfunction, neuronal dysfunction, and significant decline in cognitive impairment, primarily in the late-life populace, governing the onset of AD. Thus, HTN is an established risk factor for AD. Considering the impact of AD, 1.89 million deaths annually, and the failure of palliative therapies to cure AD, the scientific research community is looking to adopt integrated approaches to target early modified risk factors like HTN to reduce AD burden. The current review highlights the significance and impact of HTN-based prevention in lowering the AD burden in the elderly by providing a comprehensive overview of the physiological relationship between AD and HTN with an in-detail explanation of the role and applications of pathological biomarkers in this clinical association. The review will gain worth in presenting new insights and providing inclusive discussion on the correlation between HTN and cognitive impairment. It will increase across a wider scientific audience to expand understanding of this pathophysiological association. [ABSTRACT FROM AUTHOR]

An automatic detector device (ADD) has been designed and built for monitoring insulators state in overhead distribution lines. The prototyped device is suitable for measurement and analysis of the insulator leakage current (LC) on lines of distribution systems to diagnose insulator state. It operates based on two diagnostic indicators, third to fifth harmonic ratio (R3/5%) of the insulator's LC signal and cosine of phase angle difference (P.D%) between fundamental signals of the voltage and LC. Experimental data of the indicators in various conditions and various insulators are used to train a classifier for determining reference values of the indices for insulator state detection. The instrument has two physically separate parts: receiver and transmitter. They communicate via a radio communication channel which improves the effectiveness of incident management. The transmitter samples the LC signal of the target insulator using a ferrite core along with a series of active electronic filters. The sampled LC signal is then sent to the receiver. The transmitted LC signal is analyzed by the microprocessor embedded in receiver CPU. Indicators of the transmitted LC signal are calculated and compared with reference values extracted from the classifier. The receiver determines the insulator's state based on the comparison of the estimated and reference values of diagnostic indicators for the target insulator. The performance of the prototyped ADD was evaluated experimentally in the laboratory as well as on overhead distribution lines. These performance tests confirmed reliable performance of the ADD. [ABSTRACT FROM AUTHOR]