Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in neuroinflammation and Alzheimer’s disease (AD) pathophysiology, but its contribution to the phenotype associated with amyloid precursor protein (APP) overexpression remains unclear. Here, we investigated the effects of systemic IL-6 deficiency in Tg2576 mice by assessing survival, physiological parameters, behavior, learning and memory, APP/amyloid-β (Aβ)-related pathology, and gliosis in young and aged male and female mice. In this specific cohort of animals, Tg2576 mice exhibited reduced survival and body weight, together with age- and sex-dependent alterations in behavioral and cognitive parameters. Notably, despite increased circulating Aβ40 and Aβ42, Aβ40 and Aβ42 were undetectable in the brain, and amyloid plaques were absent in Tg2576 mice compared with plaque-positive control mice. IL-6 deficiency partially rescued several of these phenotypes, particularly in females. Thus, the APP overexpression-associated phenotype observed here occurred in the absence of detectable cerebral amyloidosis, highlighting that APP overexpression-associated alterations can manifest independently of amyloid plaque deposition. Together, our findings underscore the complexity of AD pathogenesis and emphasize the multifaceted nature of IL-6 in both physiological and neurodegenerative processes, particularly in the context of AD.
New discoveries are constantly being made regarding cognitive processes, pain perception, the development of degenerative diseases, brain aging, and many other functions of the nervous system. Neurogenesis plays a significant role in all of these processes. As a manifestation of brain plasticity, neurogenesis continues throughout life, and its intensity can vary depending on internal and external factors. The process by which neurons are generated can be disrupted. This depends, among other things, on age and represents one of the potential targets for interventions aimed at improving cognitive function. Inhibition of neurogenesis increases the risk of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and other conditions that lead to dependence on others in their advanced stages. The status of the neurogenesis process can be monitored by measuring the levels of mediators in the blood. The state of the brain can be influenced by providing stimuli that increase the concentration of mediators stimulating neurogenesis. People are exposed to physical factors that can inhibit the neurogenesis process, but there are also phenomena that stimulate it. Magnetic stimulation, ultrasound, electrostimulation, light therapy, normobaric and hyperbaric oxygen therapy, whole-body cryotherapy, as well as touch and vibrations, can have a significant impact on neurogenesis and accelerate this process. The aim of this study is to present the impact of physical factors on the process of neurogenesis in humans and animals, which can significantly influence the course of this process. The review uses the wording originally used in the source articles.
Nesfatin-1, an 82-amino-acid anorexigenic peptide derived from nucleobindin-2 (NUCB2), is involved in the regulation of energy homeostasis and is increasingly recognized as a modulator of reproductive function. The present study aimed to determine NUCB2 gene and protein expression in the porcine hypothalamus, examine their colocalization with gonadotropin-releasing hormone (GnRH) and kisspeptin (KISS1), and evaluate circulating nesfatin-1 levels during the estrous cycle. Analyses were performed in two hypothalamic regions: the mediobasal hypothalamus (MBH) and preoptic area (POA) collected during the cycle. In the MBH, NUCB2 gene expression was lower on days 17–19 than on the remaining examined days, whereas NUCB2 protein abundance was highest on days 2–3. In the POA, NUCB2 mRNA expression peaked on days 14–16, while the protein abundance was higher on days 10–12 than on days 14–16. In both hypothalamic regions, NUCB2/nesfatin-1 immunoreactivity overlapped with GnRH and KISS1 immunosignals. In addition, plasma nesfatin-1 concentrations were lower on days 17–19 than during the other examined stages of the cycle. Overall, these findings demonstrate cycle-dependent, region-specific expression of NUCB2/nesfatin-1 in the porcine hypothalamus and support a potential association of nesfatin-1 with hypothalamic pathways involved in reproductive regulation.
Advanced heart failure (HF) left ventricular assist device (LVAD) support and heart transplantation (HTx) are commonly considered distinct clinical stages, although each occurs within an immune system shaped by preceding inflammatory and antigenic exposures. This review introduces the concept of the recipient immune biography, describing the cumulative immunological history that accompanies patients from advanced HF through mechanical circulatory support to transplantation. We examine how HF-associated innate and adaptive immune activation may be modified by mechanical unloading while simultaneously being reshaped by blood–device interactions, hemolysis, complement activation, infection, transfusion, and sensitization during LVAD support. Following transplantation, this preconditioned immune repertoire encounters persistent donor alloantigen through direct, indirect, and semidirect allorecognition. We integrate T-cell effector, regulatory, exhaustion-associated, and memory states with T follicular helper–B-cell interactions, plasma-cell persistence, donor-specific antibodies, and tissue-resident immunity. Emphasis is placed on the limitations of peripheral biomarkers for representing graft-localized immune processes. We propose a Longitudinal Immune Trajectory integrating serial peripheral biomarkers with cellular, clonal, molecular, and spatial profiling to reconstruct patient-specific immune remodeling across the HF–LVAD–HTx continuum.
Excitotoxicity constitutes a core pathological mechanism in cerebral ischemia and other central nervous system disorders. Astrocytes serve as pivotal regulators of glutamate–glutamine cycle homeostasis and thereby play a critical role in mitigating excitotoxicity. This study established a rat thromboembolic stroke model via autologous thrombus induction and systematically investigated the mechanisms underlying adenosine-mediated neuroprotection through pharmacological modulation of the adenosine pathway using adenosine, dipyridamole, and selective adenosine receptor antagonists. Subsequently, light-sensitive opsin expression in astrocytes was driven by the GFAP promoter, enabling cell-type-specific optogenetic modulation of astrocyte activity. Our findings demonstrate that adenosine significantly attenuates cerebral injury in a rat model of thromboembolic stroke, with astrocytes identified as the primary cellular target. Adenosine elicits an anti-excitotoxic effect by coordinately upregulating GLT-1 protein expression and downregulating Cx43 protein expression in astrocytes, thereby regulating glutamate transport and diffusion. Moreover, our findings demonstrate that adenosine-mediated neuroprotection is significantly attenuated by SCH58261 but not by PSB1115. We conclude that the adenosine–A2A receptor system plays a critical role in the regulation of glutamate homeostasis.
