Phosphorylation of the α-chain in the integrin LFA-1 enables β2-chain phosphorylation and α-actinin binding required for cell adhesion

The integrin leukocyte function-associated antigen-1 (LFA-1) plays a pivotal role in leukocyte adhesion and migration, but the mechanism(s) by which this integrin is regulated has remained incompletely understood. LFA-1 integrin activity requires phosphorylation of its 2-chain and interactions of its cytoplasmic tail with various cellular proteins. The -chain is constitutively phosphorylated and necessary for cellular adhesion, but how the -chain regulates adhesion has remained enigmatic. We now show that substitution of the -chain phosphorylation site (S1140A) in T cells inhibits the phosphorylation of the functionally important Thr-758 in the 2-chain, binding of -actinin and 14-3-3 protein, and expression of an integrin-activating epitope after treatment with the stromal cell-derived factor-1. The presence of this substitution resulted in a loss of cell adhesion and directional cell migration. Moreover, LFA-1 activation through the T-cell receptor in cells expressing the S1140A LFA-1 variant resulted in less Thr-758 phosphorylation, -actinin and talin binding, and cell adhesion. The finding that the LFA-1 -chain regulates adhesion through the -chain via specific phosphorylation at Ser-1140 in the -chain has not been previously reported and emphasizes that both chains are involved in the regulation of LFA-1 integrin activity.Peer reviewe

Generation of a human induced pluripotent stem cell line (UEFi003-A) carrying heterozygous A673T variant in amyloid precursor protein associated with a reduced risk of Alzheimer's disease

A673T mutation in the amyloid precursor protein (APP) is a rare variant associated with a reduced risk of late-onset Alzheimer's disease (AD) and age-related cognitive decline. The A673T mutation decreases beta-amyloid (A beta) production and aggregation in neuronal cultures in vitro. Here we have identified a Finnish non-diseased male individual carrying a heterozygous A673T mutation, obtained a skin biopsy sample from him, and generated an iPSC line using commercially available integration-free Sendai virus-based kit. The established iPSC line retained the mutation, expressed pluripotency markers, had a normal karyotype, and differentiated into all three germ layers in vitro.Peer reviewe

Human PSEN1 Mutant Glia Improve Spatial Learning and Memory in Aged Mice

The PSEN1 ΔE9 mutation causes a familial form of Alzheimer’s disease (AD) by shifting the processing of amyloid precursor protein (APP) towards the generation of highly amyloidogenic Aβ42 peptide. We have previously shown that the PSEN1 ΔE9 mutation in human-induced pluripotent stem cell (iPSC)-derived astrocytes increases Aβ42 production and impairs cellular responses. Here, we injected PSEN1 ΔE9 mutant astrosphere-derived glial progenitors into newborn mice and investigated mouse behavior at the ages of 8, 12, and 16 months. While we did not find significant behavioral changes in younger mice, spatial learning and memory were paradoxically improved in 16-month-old PSEN1 ΔE9 glia-transplanted male mice as compared to age-matched isogenic control-transplanted animals. Memory improvement was associated with lower levels of soluble, but not insoluble, human Aβ42 in the mouse brain. We also found a decreased engraftment of PSEN1 ΔE9 mutant cells in the cingulate cortex and significant transcriptional changes in both human and mouse genes in the hippocampus, including the extracellular matrix-related genes. Overall, the presence of PSEN1 ΔE9 mutant glia exerted a more beneficial effect on aged mouse brain than the isogenic control human cells likely as a combination of several factors

Neuronal ICAM-5 Inhibits Microglia Adhesion and Phagocytosis and Promotes an Anti-inflammatory Response in LPS Stimulated Microglia

The intercellular adhesion molecule-5 (ICAM-5) regulates neurite outgrowth and synaptic maturation. ICAM-5 overexpression in the hippocampal neurons induces filopodia formation in vitro. Since microglia are known to prune supernumerous synapses during development, we characterized the regulatory effect of ICAM-5 on microglia. ICAM-5 was released as a soluble protein from N-methyl-D-aspartic acid (NMDA)-treated neurons and bound by microglia. ICAM-5 promoted down-regulation of adhesion and phagocytosis in vitro. Microglia formed large cell clusters on ICAM-5-coated surfaces whereas they adhered and spread on the related molecule ICAM-1. ICAM-5 further reduced the secretion of the proinflammatory cytokines tumor necrosis factor a (TNF-alpha) and interleukin 1 beta (IL-1 beta), but on the contrary induced the secretion of the antiinflammatory IL-10 from lipopolysaccharide (LPS) stimulated microglia. Thus, ICAM-5 might be involved in the regulation of microglia in both health and disease, playing an important neuroprotective role when the brain is under immune challenges and as a "don't-eat-me" signal when it is solubilized from active synapses.Peer reviewe

NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress. Here, we show that inflammatory stimulation leads to metabolic activation of human astrocytes and reduces amyloid secretion. On the other hand, the activation of oxidative metabolism leads to increased reactive oxygen species production especially in AD astrocytes. While healthy astrocytes increase glutathione (GSH) release to protect the cells, Presenilin‐1‐mutated AD patient astrocytes do not. Thus, chronic inflammation is likely to induce oxidative damage in AD astrocytes. Activation of NRF2, the major regulator of cellular antioxidant defenses, encoded by the NFE2L2 gene, poses several beneficial effects on AD astrocytes. We report here that the activation of NRF2 pathway reduces amyloid secretion, normalizes cytokine release, and increases GSH secretion in AD astrocytes. NRF2 induction also activates the metabolism of astrocytes and increases the utilization of glycolysis. Taken together, targeting NRF2 in astrocytes could be a potent therapeutic strategy in AD.</p

Health Literacy, Self-Perceived Health, and Substance Use Behavior among Young People with Alcohol and Substance Use Disorders

Licit and illicit substance use is one of the major public health issues with severe negative health consequences for individuals and society. Health literacy is essential for improving one’s health and navigation in the healthcare system. However, the evidence of health literacy in people with substance use disorders is limited. This study aims to examine health literacy and its socio-demographic, health-related, and substance use-related correlates in young people with alcohol (AUD) and substance use disorders (SUD). In this study, cross-sectional data of young people undergoing addiction treatment for AUD (N = 201, mean age 37.6) and SUD (N = 165, mean age 31.1) were used. Health literacy was assessed using the HLS-EU-Q47. Simple and multiple linear regression was performed to estimate the correlates of health literacy. In total, 37.8% of participants with AUD and 41.8% of SUD had limited health literacy. In participants with AUD, living condition factors, self-perceived health indicators, and frequency of alcohol use showed a significant effect on health literacy. In participants with SUD, financial factors, self-perceived health indicators, and injection sharing showed a significant effect. Increasing health literacy might contribute to improved health outcomes and decreased high-risk substance use-related behavior in people undergoing addiction treatment

Metabolic and immune dysfunction of glia in neurodegenerative disorders : Focus on iPSC models

The research on neurodegenerative disorders has long focused on neuronal pathology and used transgenic mice as disease models. However, our understanding of the chronic neurodegenerative process in the human brain is still very limited. It is increasingly recognized that neuronal loss is not caused solely by intrinsic degenerative processes but rather via impaired interactions with surrounding glia and other brain cells. Dysfunctional astrocytes do not provide sufficient nutrients and antioxidants to the neurons, while dysfunctional microglia cannot efficiently clear pathogens and cell debris from extracellular space, thus resulting in chronic inflammatory processes in the brain. Importantly, human glia, especially the astrocytes, differ significantly in morphology and function from their mouse counterparts, and therefore more human-based disease models are needed. Recent advances in stem cell technology make it possible to reprogram human patients' somatic cells to induced pluripotent stem cells (iPSC) and differentiate them further into patient-specific glia and neurons, thus providing a virtually unlimited source of human brain cells. This review summarizes the recent studies using iPSC-derived glial models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis and discusses the applicability of these models to drug testing. This line of research has shown that targeting glial metabolism can improve the survival and function of cocultured neurons and thus provide a basis for future neuroprotective treatments.Peer reviewe

MATEMATIK INDUKSIYA METODI VA UNING DASTURLASHGA TADBIQI

Ushbu maqolada matematik induksiya metodi haqida bayon etilgan. Asosiy tushunchalarga to`xtalib o`tilgan va bir nechta misollarning yechimi ko`rsatilib, matematik induksiya metodi yordamida isbotlangan va dasturi tuzib ko`rsatilgan