Increased levels of circulating fatty acids, such as palmitic acid (PA), are associated with the development of obesity, insulin resistance, type-2 diabetes and metabolic syndrome. Furthermore, these diseases are linked to an increased risk of cancer, cardiovascular diseases, mild cognitive impairment and even Alzheimer's disease (AD). However, the precise actions of elevated PA levels on neurons and their association with neuronal metabolic disruption that leads to the expression of pathological markers of AD, such as the overproduction and accumulation of the amyloid-β peptide, represent an area of intense investigation. A possible molecular mechanism involved in the effects of PA may be through dysfunction of the NAD + sensor enzyme, SIRT1. Therefore, the aim of the present study was to analyze the relationship between the effects of PA metabolism on the function of SIRT1 and the upregulation of BACE1 in cultured hippocampal neurons. PA reduced the total amount of NAD + in neurons that caused an increase in p65 K310 acetylation due to inhibition of SIRT1 activity and low protein content. Furthermore, BACE1 protein and its activity were increased, and BACE1 was relocated in neurites after PA exposure.
Adult hippocampal neurogenesis is a finely tuned process regulated by extrinsic factors. Neuroinflammation is a hallmark of several pathological conditions underlying dysregulation of neurogenesis. In animal models, lipopolysaccharide (LPS)-induced neuroinflammation leads to a neurogenic decrease mainly associated to the early inflammatory response. However, it is not well understood how the neuroinflammatory response progresses over time and if neurogenesis continues to be diminished during the late neuroinflammatory response. Moreover, it is unknown if repeated intermittent administration of LPS along time induces a greater reduction in neurogenesis. We administered one single intraperitoneal injection of LPS or saline or four repeated injections (one per week) of LPS or saline to young-adult mice. A cohort of new cells was labeled with three 5-bromo-2-deoxyuridine injections (one per day) 4 days after the last LPS injection. We evaluated systemic and neuroinflammation-associated parameters and compared the effects of the late neuroinflammatory response on neurogenesis induced by each protocol. Our results show that 1) a single LPS injection leads to a late pro-inflammatory response characterized by microglial activation, moderate astrocytic reaction and increased interleukin-6 levels. This response correlates in time with decreased neurogenesis and 2) a repeated intermittent injection of LPS does not elicit a late pro-inflammatory response although activated microglia persists. The latter profile is not accompanied by a continued long-term hippocampal neurogenic decrease. Hereby, we provide evidence that the neuroinflammatory response is a dynamic process that progresses in a milieu-dependent manner and does not necessarily lead to a neurogenic decrease, highlighting the complex interaction between the immune system and neurogenesis.
Neuronal activity in the retina generates osmotic gradients that lead to Müller cell swelling, followed by a regulatory volume decrease (RVD) response, partially due to the isoosmotic efflux of KCl and water. However, our previous studies in a human Müller cell line (MIO-M1) demonstrated that an important fraction of RVD may also involve the efflux of organic solutes. We also showed that RVD depends on the swelling-induced Ca release from intracellular stores. Here we investigate the contribution of taurine (Tau) and glutamate (Glu), the most relevant amino acids in Müller cells, to RVD through the volume-regulated anion channel (VRAC), as well as their Ca dependency in MIO-M1 cells. Swelling-induced [H]Tau/[H]Glu release was assessed by radiotracer assays and cell volume by fluorescence videomicroscopy. Results showed that cells exhibited an osmosensitive efflux of [H]Tau and [H]Glu (Tau > Glu) blunted by VRAC inhibitors 4-(2-butyl-6,7-dichloro-2-cyclopentylindan-1-on-5-yl)-oxybutyric acid and carbenoxolone reducing RVD. Only [H]Tau efflux was mainly dependent on Ca release from intracellular stores. RVD was unaffected in a Ca-free medium, probably due to Ca-independent Tau and Glu release, but was reduced by chelating intracellular Ca. The inhibition of phosphatidylinositol-3-kinase reduced [H]Glu efflux but also the Ca-insensitive [H]Tau fraction and decreased RVD, providing evidence of the relevance of this Ca-independent pathway. We propose that VRAC-mediated Tau and Glu release has a relevant role in RVD in Müller cells. The observed disparities in Ca influence on amino acid release suggest the presence of VRAC isoforms that may differ in substrate selectivity and regulatory mechanisms, with important implications for retinal physiology. NEW & NOTEWORTHY The mechanisms for cell volume regulation in retinal Müller cells are still unknown. We show that swelling-induced taurine and glutamate release mediated by the volume-regulated anion channel (VRAC) largely contributes the to the regulatory volume decrease response in a human Müller cell line. Interestingly, the hypotonic-induced efflux of these amino acids exhibits disparities in Ca-dependent and -independent regulatory mechanisms, which strongly suggests that Müller cells may express different VRAC heteromers formed by the recently discovered leucine-rich repeat containing 8 (LRRC8) proteins.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.