The amyloid precursor protein and its derived fragments concomitantly contribute to the alterations of mitochondrial transport machinery in Alzheimer's disease.

Mitochondria dysfunctions and mitophagy failure have been associated with several Alzheimer's disease (AD) related molecular actors including amyloid beta (Aβ) and recently the amyloid precursor protein-C terminal fragments (APP-CTFs). The efficacy of the mitophagy process in neurons relies on regulated mitochondrial transport along axons involving a complex molecular machinery. The contribution of the amyloid precursor protein (APP) and its derived fragments to the mitochondrial transport machinery alterations in AD have not been investigated before.

Effect of Ouabain on Glutamate Transport in the Hippocampus of Rats with LPS-Induced Neuroinflammation.

A lipopolysaccharide (LPS)-induced neuroinflammation rat model was used to study the effects of ouabain (OUA) at low concentrations, which can interact with the Na,K-ATPase, causing the modulation of intracellular signalling pathways in the Central Nervous System. Our study aimed to analyse the effects of OUA on glutamate transport in the hippocampus of rats with LPS-induced neuroinflammation. Adult male Wistar rats were divided into four groups: OUA (1.

Consequences of the Lack of TNFR1 in Ouabain Response in the Hippocampus of C57BL/6J Mice.

Ouabain is a cardiac glycoside that has a protective effect against neuroinflammation at low doses through Na/K-ATPase signaling and that can activate tumor necrosis factor (TNF) in the brain. TNF plays an essential role in neuroinflammation and regulates glutamate receptors by acting on two different receptors (tumor necrosis factor receptor 1 [TNFR1] and TNFR2) that have distinct functions and expression. The activation of constitutively and ubiquitously expressed TNFR1 leads to the expression of pro-inflammatory cytokines.

Neuroprotective action of α-Klotho against LPS-activated glia conditioned medium in primary neuronal culture.

The α-Klotho is an anti-aging protein that, when overexpressed, extends the life span in humans and mice. It has an anti-inflammatory and protective action on renal cells by inhibiting NF-κB activation and production of inflammatory cytokines in response to TNF-α. Furthermore, studies have shown the neuroprotective effect of α-Klotho against neuroinflammation on different conditions, such as aging, animal models of neurodegenerative diseases, and ischemic brain injury.

A missense mutation converts the Na,K-ATPase into an ion channel and causes therapy-resistant epilepsy.

The ion pump Na,K-ATPase is a critical determinant of neuronal excitability; however, its role in the etiology of diseases of the central nervous system (CNS) is largely unknown. We describe here the molecular phenotype of a Trp931Arg mutation of the Na,K-ATPase catalytic α1 subunit in an infant diagnosed with therapy-resistant lethal epilepsy. In addition to the pathological CNS phenotype, we also detected renal wasting of Mg.

The Role of GPNMB in Inflammation.

Inflammation is a response to a lesion in the tissue or infection. This process occurs in a specific manner in the central nervous system and is called neuroinflammation, which is involved in neurodegenerative diseases. GPNMB, an endogenous glycoprotein, has been recently related to inflammation and neuroinflammation.

Toll-like Receptor 4 Signaling is Critical for the Adaptive Cellular Stress Response Effects Induced by Intermittent Fasting in the Mouse Brain.

Among different kinds of dietary energy restriction, intermittent fasting (IF) has been considered a dietary regimen which causes a mild stress to the organism. IF can stimulate proteins and signaling pathways related to cell stress that can culminate in the increase of the body resistance to severe stress conditions. Energy intake reduction induced by IF can induce modulation of receptors, kinases, and phosphatases, which in turn can modulate the activation of transcription factors such as NF-E2-related factor 2 (NRF2) and cAMP response element-binding (CREB) which regulate the transcription of genes related to the translation of proteins such as growth factors: brain-derived neurotrophic factor (BDNF), chaperone proteins: heat shock proteins (HSP), and so on.

The Janus face of ouabain in Na /K -ATPase and calcium signalling in neurons.

Na /K -ATPase, a transmembrane protein essential for maintaining the electrochemical gradient across the plasma membrane, acts as a receptor for cardiotonic steroids such as ouabain. Cardiotonic steroids binding to Na /K -ATPase triggers signalling pathways or inhibits Na /K -ATPas activity in a concentration-dependent manner, resulting in a modulation of Ca levels, which are essential for homeostasis in neurons. However, most of the pharmacological strategies for avoiding neuronal death do not target Na /K -ATPase activity due to its complexity and the poor understanding of the mechanisms involved in Na /K -ATPase modulation.

Molecular Dysfunctions of Mitochondria-Associated Membranes (MAMs) in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative pathology characterized by a progressive decline of cognitive functions. Alteration of various signaling cascades affecting distinct subcellular compartment functions and their communication likely contribute to AD progression. Among others, the alteration of the physical association between the endoplasmic reticulum (ER) and mitochondria, also reffered as mitochondria-associated membranes (MAMs), impacts various cellular housekeeping functions such as phospholipids-, glucose-, cholesterol-, and fatty-acid-metabolism, as well as calcium signaling, which are all altered in AD.

Tumor necrosis factor receptor-associated factor 6 interaction with alpha-synuclein enhances cell death through the Nuclear Factor-kB pathway.

Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by intracellular inclusions named Lewy bodies (LB), and alpha-synuclein (asyn) is the major component of these protein aggregates. The precise physiological and pathological roles of asyn are not fully understood. Nevertheless, asyn present in LB is ubiquitinated but fails to reach the 26S proteasome.

Ouabain attenuates oxidative stress and modulates lipid composition in hippocampus of rats in lipopolysaccharide-induced hypocampal neuroinflammation in rats.

Our study aimed to analyze the effect of ouabain (OUA) administration on lipopolysaccharide (LPS)-induced changes in hippocampus of rats. Oxidative parameters were analyzed in Wistar rats after intraperitoneal injection of OUA (1.8 µg/kg), LPS (200 µg/kg), or OUA plus LPS or saline.

Ouabain increases neuronal branching in hippocampus and improves spatial memory.

Previous research shows Ouabain (OUA) to bind Na, K-ATPase, thereby triggering a number of signaling pathways, including the transcription factors NFᴋB and CREB. These transcription factors play a key role in the regulation of BDNF and WNT-β-catenin signaling cascades, which are involved in neuroprotection and memory regulation. This study investigated the effects of OUA (10 nM) in the modulation of the principal signaling pathways involved in morphological plasticity and memory formation in the hippocampus of adult rats.

Ouabain attenuates the oxidative stress induced by lipopolysaccharides in the cerebellum of rats.

Our study aimed to analyze the effect of ouabain administration on lipopolysaccharide (LPS)-induced changes in oxidative parameters, membrane lipid composition, and the activities of some important enzymes of the nervous system. The content of phospholipids, cholesterol, and gangliosides were analyzed in Wistar rats after intraperitoneal injection of ouabain (1.8 μg/kg), LPS (200 μg/kg), or saline.

Alpha 2 Na,K-ATPase silencing induces loss of inflammatory response and ouabain protection in glial cells.

Ouabain (OUA) is a cardiac glycoside that binds to Na,K-ATPase (NKA), a conserved membrane protein that controls cell transmembrane ionic concentrations and requires ATP hydrolysis. At nM concentrations, OUA activates signaling pathways that are not related to its typical inhibitory effect on the NKA pump. Activation of these signaling pathways protects against some types of injury of the kidneys and central nervous system.

The Influence of Na(+), K(+)-ATPase on Glutamate Signaling in Neurodegenerative Diseases and Senescence.

Decreased Na(+), K(+)-ATPase (NKA) activity causes energy deficiency, which is commonly observed in neurodegenerative diseases. The NKA is constituted of three subunits: α, β, and γ, with four distinct isoforms of the catalytic α subunit (α1-4). Genetic mutations in the ATP1A2 gene and ATP1A3 gene, encoding the α2 and α3 subunit isoforms, respectively can cause distinct neurological disorders, concurrent to impaired NKA activity.

Cardiotonic Steroids as Modulators of Neuroinflammation.

Cardiotonic steroids (CTS) are a class of specific ligands of the Na(+), K(+)- ATPase (NKA). NKA is a P-type ATPase that is ubiquitously expressed and although well known to be responsible for the maintenance of the cell electrochemical gradient through active transport, NKA can also act as a signal transducer in the presence of CTS. Inflammation, in addition to importantly driving organism defense and survival mechanisms, can also modulate NKA activity and memory formation, as well as being relevant to many chronic illnesses, neurodegenerative diseases, and mood disorders.

Ouabain Modulates the Lipid Composition of Hippocampal Plasma Membranes from Rats with LPS-induced Neuroinflammation.

The effects of ouabain (OUA) and lipopolysaccharide (LPS) in vivo on hippocampal membranes (RHM) of Wistar male rats aged 3 months were analyzed. After intraperitoneal (i.p.

Effects of intermittent fasting on age-related changes on Na,K-ATPase activity and oxidative status induced by lipopolysaccharide in rat hippocampus.

Chronic neuroinflammation is a common characteristic of neurodegenerative diseases, and lipopolysaccharide (LPS) signaling is linked to glutamate-nitric oxide-Na,K-ATPase isoforms pathway in central nervous system (CNS) and also causes neuroinflammation. Intermittent fasting (IF) induces adaptive responses in the brain that can suppress inflammation, but the age-related effect of IF on LPS modulatory influence on nitric oxide-Na,K-ATPase isoforms is unknown. This work compared the effects of LPS on the activity of α1,α2,3 Na,K-ATPase, nitric oxide synthase gene expression and/or activity, cyclic guanosine monophosphate, 3-nitrotyrosine-containing proteins, and levels of thiobarbituric acid-reactive substances in CNS of young and older rats submitted to the IF protocol for 30 days.

Signaling function of Na,K-ATPase induced by ouabain against LPS as an inflammation model in hippocampus.

Background: Ouabain (OUA) is a newly recognized hormone that is synthesized in the adrenal cortex and hypothalamus. Low doses of OUA can activate a signaling pathway by interaction with Na,K-ATPase, which is protective against a number of insults. OUA has central and peripheral anti-inflammatory effects.