Embryonic-Derived Myb− Macrophages Enhance Bacterial Clearance and Improve Survival in Rat Sepsis

Peritoneal resident macrophages play a key role in combating sepsis in the peritoneal cavity. We sought to determine if peritoneal transplantation of embryonic Myb⁻ “peritoneal-like” macrophages attenuate abdominal fecal sepsis. Directed differentiation of rodent pluripotent stem cells (PSCs) was used in factor-defined media to produce embryonic-derived large “peritoneal-like” macrophages (Ed-LPM) that expressed peritoneal macrophage markers and demonstrated phagocytic capacity. Preclinical in vivo studies determined Ed-LPM efficacy in rodent abdominal fecal sepsis with or without Meropenem. Ex vivo studies explored the mechanism and effects of Ed-LPM on host immune cell number and function, including phagocytosis, reactive oxygen species (ROS) production, efferocytosis and apoptosis. Ed-LPM reduced sepsis severity by decreasing bacterial load in the liver, spleen and lungs. Ed-LPM therapy significantly improved animal survival by ~30% and reduced systemic bacterial burden to levels comparable to Meropenem therapy. Ed-LPM therapy decreased peritoneal TNFα while increasing IL-10 concentrations. Ed-LPMs enhanced peritoneal macrophage phagocytosis of bacteria, increased macrophage production of ROS and restored homeostasis via apoptosis and efferocytosis-induced clearance of neutrophils. In conclusion, Ed-LPM reduced systemic sepsis severity, improved survival and reduced bacterial load by enhancing peritoneal macrophage bacterial phagocytosis and killing and clearance of intra-peritoneal neutrophils. Macrophage therapy may be a potential strategy to address sepsis.     

Signaling Transduction of ABA,ROS, and Ca2+ in Plant Stomatal Closure in Response to Drought

Drought is a global threat that affects agricultural production. Plants have evolved several adaptive strategies to cope with drought. Stomata are essential structures for plants to control water status and photosynthesis rate. Stomatal closure is an efficient way for plants to reduce water loss and improve survivability under drought conditions. The opening and closure of stomata depend on the turgor pressure in guard cells. Three key signaling molecules, including abscisic acid (ABA), reactive oxygen species (ROS), and calcium ion (Ca²⁺), play pivotal roles in controlling stomatal closure. Plants sense the water-deficit signal mainly via leaves and roots. On the one hand, ABA is actively synthesized in root and leaf vascular tissues and transported to guard cells. On the other hand, the roots sense the water-deficit signal and synthesize CLAVATA3/EMBRYO-SURROUNDING REGION RELATED 25 (CLE25) peptide, which is transported to the guard cells to promote ABA synthesis. ABA is perceived by pyrabactin resistance (PYR)/PYR1-like (PYL)/regulatory components of ABA receptor (RCAR) receptors, which inactivate PP2C, resulting in activating the protein kinases SnRK2s. Many proteins regulating stomatal closure are activated by SnRK2s via protein phosphorylation. ABA-activated SnRK2s promote apoplastic ROS production outside of guard cells and transportation into the guard cells. The apoplastic H₂O₂ can be directly sensed by a receptor kinase, HYDROGEN PEROXIDE-INDUCED CA²⁺ INCREASES1 (HPCA1), which induces activation of Ca²⁺ channels in the cytomembrane of guard cells, and triggers an increase in Ca²⁺ in the cytoplasm of guard cells, resulting in stomatal closure. In this review, we focused on discussing the signaling transduction of ABA, ROS, and Ca²⁺ in controlling stomatal closure in response to drought. Many critical genes are identified to have a function in stomatal closure under drought conditions. The identified genes in the process can serve as candidate genes for genetic engineering to improve drought resistance in crops. The review summarizes the recent advances and provides new insights into the signaling regulation of stomatal closure in response to water-deficit stress and new clues on the improvement of drought resistance in crops.     

Oxidative Stress Orchestrates MAPK and Nitric-Oxide Synthase Signal

Reactive oxygen species (ROS) are not only harmful to cell survival but also essential to cell signaling through cysteine-based redox switches. In fact, ROS triggers the potential activation of mitogen-activated protein kinases (MAPKs). The 90 kDa ribosomal S6 kinase 1 (RSK1), one of the downstream mediators of the MAPK pathway, is implicated in various cellular processes through phosphorylating different substrates. As such, RSK1 associates with and phosphorylates neuronal nitric oxide (NO) synthase (nNOS) at Ser847, leading to a decrease in NO generation. In addition, the RSK1 activity is sensitive to inhibition by reversible cysteine-based redox modification of its Cys223 during oxidative stress. Aside from oxidative stress, nitrosative stress also contributes to cysteine-based redox modification. Thus, the protein kinases such as Ca²⁺/calmodulin (CaM)-dependent protein kinase I (CaMKI) and II (CaMKII) that phosphorylate nNOS could be potentially regulated by cysteine-based redox modification. In this review, we focus on the role of post-translational modifications in regulating nNOS and nNOS-phosphorylating protein kinases and communication among themselves.     

Helicobacter pylori Neutrophil-Activating Protein Directly Interacts with and Activates Toll-like Receptor 2 to Induce the Secretion of Interleukin-8 from Neutrophils and ATRA-Induced Differentiated HL-60 Cells

Helicobacter pylori neutrophil-activating protein (HP-NAP)-induced production of reactive oxygen species (ROS) by neutrophils and monocytes is regulated by pertussis toxin (PTX)-sensitive G proteins, whereas HP-NAP-induced cytokine secretion by monocytes is mediated by Toll-like receptor 2 (TLR2). However, it is unclear whether TLR2 participates in HP-NAP-induced cytokine secretion by neutrophils. Here, all-trans retinoic acid (ATRA)-induced differentiated HL-60 cells were first employed as a neutrophil model to investigate the molecular mechanisms underlying neutrophil responses to HP-NAP. HP-NAP-induced ROS production in ATRA-induced differentiated HL-60 cells is mediated by the PTX-sensitive heterotrimeric G protein-dependent activation of extracellular signal-regulated kinase 1/2 and p38-mitogen-activated protein kinase, which is consistent with the findings reported for human neutrophils. Next, whether TLR2 participated in HP-NAP-induced secretion of interleukin-8 (IL-8) was investigated in neutrophils and ATRA-induced differentiated HL-60 cells. In both cells, TLR2 participated in HP-NAP-induced IL-8 secretion but not HP-NAP-induced ROS production. Interestingly, PTX-sensitive G proteins also contributed to the HP-NAP-induced secretion of IL-8 from neutrophils and the differentiated HL-60 cells. Our ELISA-based binding assay further revealed the competitive binding of Pam₃CSK₄, a TLR2 agonist, and HP-NAP to TLR2, which suggests the presence of specific and direct interactions between HP-NAP and TLR2. Thus, HP-NAP directly interacts with and activates TLR2 to induce IL-8 secretion in neutrophils and ATRA-induced differentiated HL-60 cells.     

Ouabain-Induced Changes in the Expression of Voltage-Gated Potassium Channels in Epithelial Cells Depend on Cell–Cell Contacts

Ouabain is a cardiac glycoside, initially isolated from plants, and currently thought to be a hormone since some mammals synthesize it endogenously. It has been shown that in epithelial cells, it induces changes in properties and components related to apical–basolateral polarity and cell–cell contacts. In this work, we used a whole-cell patch clamp to test whether ouabain affects the properties of the voltage-gated potassium currents (Ik) of epithelial cells (MDCK). We found that: (1) in cells arranged as mature monolayers, ouabain induced changes in the properties of Ik; (2) it also accelerated the recovery of Ik in cells previously trypsinized and re-seeded at confluence; (3) in cell–cell contact-lacking cells, ouabain did not produce a significant change; (4) Na⁺/K⁺ ATPase might be the receptor that mediates the effect of ouabain on Ik; (5) the ouabain-induced changes in Ik required the synthesis of new nucleotides and proteins, as well as Golgi processing and exocytosis, as evidenced by treatment with drugs inhibiting those processes; and (5) the signaling cascade included the participation of cSrC, PI3K, Erk1/2, NF-κB and β-catenin. These results reveal a new role for ouabain as a modulator of the expression of voltage-gated potassium channels, which require cells to be in contact with themselves.     

Proton conducting membranes based on semi-interpenetrating polymer network of Nafion and polybenzimidazole

A new strategy to prepare the reinforced composite membranes for polymer electrolyte membrane fuel cells (PEMFCs), which can work both in humidified and anhydrous state, was proposed via constructing semi-interpenetrating polymer network (semi-IPN) structure from polybenzimidazole (PBI) and Nafion^®212, with N-vinylimidazole as the crosslinker. The crosslinkable PBI was synthesized from poly(2,2′-(m-phenylene)-5,5′-bibenzimidazole) and p-vinylbenzyl chloride. The semi-IPN structure was formed during the membrane preparation. The composite membranes exhibit excellent thermal stability, high-dimensional stability, and significantly improved mechanical properties compared with Nafion^®212. The proton transport in the hydrated composite membranes is mainly contributed by the vehicle mechanism, with proton conductivity from ∼10⁻² S/cm to ∼10⁻¹ S/cm. When the temperature exceeds 100 °C, the proton conductivity of the semi-IPN membranes decreases quickly due to the dehydration of the membranes. Under anhydrous condition, the proton conductivity of the membranes will drop to ∼10⁻⁴ S/cm, which is also useful for intermediate temperature (100-200 °C) PEMFCs. The benzimidazole structure of PBI and the acidic component of Nafion^® provide the possibility for the proton mobility via structure diffusion involving proton transfer between the heterocycles with a corresponding reorganization of the hydrogen bonded network.     

Protectin DX, a Double Lipoxygenase Product of DHA, Inhibits Both ROS Production in Human Neutrophils and Cyclooxygenase Activities

Neutrophils play a major role in inflammation by releasing large amounts of reactive oxygen species (ROS) produced by NADPH oxidase (NOX) and myeloperoxidase (MPO). This ROS overproduction is mediated by phosphorylation of the NOX subunits in an uncontrolled manner. Therefore, targeting neutrophil subunits would represent a promising strategy to moderate NOX activity, lower ROS, and other inflammatory agents, such as cytokines and leukotrienes, produced by neutrophils. For this purpose, we investigated the effects of protectin DX (PDX)—a docosahexaenoic acid di-hydroxylated product which inhibits blood platelet aggregation—on neutrophil activation in vitro. We found that PDX decreases ROS production, inhibits NOX activation and MPO release from neutrophils. We also confirm, that PDX is an anti-aggregatory and anti-inflammatory agent by inhibiting both cyclooxygenase-1 and -2 (COX-1 and COX-2, E.C. 1.14.99.1) as well as COX-2 in lipopolysaccharides-treated human neutrophils. However, PDX has no effect on the 5-lipoxygenase pathway that produces the chemotactic agent leukotriene B₄ (LTB₄). Taken together, our results suggest that PDX could be a protective agent against neutrophil invasion in chronic inflammatory diseases.     

Modulation of Cellular NAD+ Attenuates Cancer-Associated Hypercoagulability and Thrombosis via the Inhibition of Tissue Factor and Formation of Neutrophil Extracellular Traps

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD⁺) levels by accelerating the oxidation of NADH to NAD⁺, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD⁺ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD⁺ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD⁺ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.     

Lack of Functional P110δ Affects Expression of Activation Marker CD80 but Does Not Influence Functions of Neutrophils

Neutrophils are specialized immune cells that are essential constituents of the innate immune response. They defend the organism against pathogens through various mechanisms. It was reported that phosphatidylinositols are key players in neutrophil functions, especially in the activity of class-I phosphoinositide 3-kinases (PI3Ks). P110δ, one of the PI3K subunits, is mostly expressed in immune cells, and its activity plays an important role in inflammatory responses. The aim of this study was to investigate the role of p110δ in neutrophil antimicrobial functions, activation status and cytokine production. To this end, we used bone marrow and splenic neutrophils isolated from a murine model expressing catalytically inactive p110δ^D910A/D910A. The level of phagocytosis and degranulation, the expressions of activation markers and cytokine production were determined by flow cytometry. ROS generation and NET release were assessed by fluorometry and fluorescent microscopy. We observed a significantly higher percentage of CD80-positive cells among the splenic granulocytes and found granulocytes subpopulations of differing phenotypes between WT and p110δ^D910A/D910A mice by multiparametric tSNE analysis. Moreover, we detected some differences in the expressions of activation markers, intracellular production of cytokines and bacterial killing. However, we did not observe any alterations in the selected neutrophil functions in p110δ mutant mice. Altogether, our data suggest that the catalytic p110 subunit(s), other than p110δ, is a key player in most neutrophil functions in mice. A follow-up study to correlate these in vitro results with in vivo observations is highly recommended.     

Zearalenone Induces MLKL-Dependent Necroptosis in Goat Endometrial Stromal Cells via the Calcium Overload/ROS Pathway

Zearalenone (ZEA) is a fungal mycotoxin known to exert strong reproductive toxicity in animals. As a newly identified type of programmed cell death, necroptosis is regulated by receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed-lineage kinase domain-like pseudokinase (MLKL). However, the role and mechanism of necroptosis in ZEA toxicity remain unclear. In this study, we confirmed the involvement of necroptosis in ZEA-induced cell death in goat endometrial stromal cells (gESCs). The release of lactate dehydrogenase (LDH) and the production of PI-positive cells markedly increased. At the same time, the expression of RIPK1 and RIPK3 mRNAs and P-RIPK3 and P-MLKL proteins were significantly upregulated in ZEA-treated gESCs. Importantly, the MLKL inhibitor necrosulfonamide (NSA) dramatically attenuated gESCs necroptosis and powerfully blocked ZEA-induced reactive oxygen species (ROS) generation and mitochondrial dysfunction. The reactive oxygen species (ROS) scavengers and N-acetylcysteine (NAC) inhibited ZEA-induced cell death. In addition, the inhibition of MLKL alleviated the intracellular Ca²⁺ overload caused by ZEA. The calcium chelator BAPTA-AM markedly suppressed ROS production and mitochondrial damage, thus inhibiting ZEA-induced necroptosis. Therefore, our results revealed the mechanism by which ZEA triggers gESCs necroptosis, which may provide a new therapeutic strategy for ZEA poisoning.     

Copper(I/II), α/β‐Synuclein and Amyloid‐β: Menage à Trois?

Copper binding to α‐synuclein (aS) and to amyloid‐β (Ab) has been connected to Parkinson's and Alzheimer's disease (AD), respectively, because Cu ions can modulate the peptide aggregation, and these Cu ? peptide complexes can catalyse the production of reactive oxygen species (ROS). In a significant proportion of AD brains, aggregation of aS and Ab has been detected, and it was proposed that Ab and aS interact with each other. Thus, we investigated the potential interactions of Ab and aS through their binding of copper(I) and copper(II). Additionally, β‐synuclein (bS) was investigated, due to its additional methionine residue, a potential Cu^I ligand. We found that: 1) the peptides containing the Cu‐binding domains Ab1–16, aS1–15 and bS1–15 have similar affinities towards Cu^II and towards Cu^I, with Ab1–16 being slightly stronger, 2) in the case of Cu^I, the additional Met residue in bS1–15 increased the affinity slightly, 3) the exchange of Cu^I/II between the two peptides is rapid (≤ms), 4) a/bS1–15 and Ab1–16 form a heterodimeric complex with Cu^II, 5) Cu^I probably promotes a transient ternary complex, 6) the different Cu^I/II coordination of Ab1–16, aS1–15 and bS1–15 impacts the capacity to produce ROS and to oxidise catechol, and 7) when Ab1–16, aS1–15 and Cu are present, the ROS production more closely resembles that by Ab1–16. The work gives insights into the coordination chemistry of these related peptides, and the relevance of coordination differences, the ternary complex and ROS production are discussed.     

The Role of Cell Cycle Regulators in Cell Survival—Dual Functions of Cyclin-Dependent Kinase 20 and p21Cip1/Waf1

The mammalian cell cycle is important in controlling normal cell proliferation and the development of various diseases. Cell cycle checkpoints are well regulated by both activators and inhibitors to avoid cell growth disorder and cancerogenesis. Cyclin dependent kinase 20 (CDK20) and p21^Cip1/Waf1 are widely recognized as key regulators of cell cycle checkpoints controlling cell proliferation/growth and involving in developing multiple cancers. Emerging evidence demonstrates that these two cell cycle regulators also play an essential role in promoting cell survival independent of the cell cycle, particularly in those cells with a limited capability of proliferation, such as cardiomyocytes. These findings bring new insights into understanding cytoprotection in these tissues. Here, we summarize the new progress of the studies on these two molecules in regulating cell cycle/growth, and their new roles in cell survival by inhibiting various cell death mechanisms. We also outline their potential implications in cancerogenesis and protection in heart diseases. This information renews the knowledge in molecular natures and cellular functions of these regulators, leading to a better understanding of the pathogenesis of the associated diseases and the discovery of new therapeutic strategies.     

Suppressive Role of Bam32/DAPP1 in Chemokine-Induced Neutrophil Recruitment

Bam32 (B cell adaptor molecule of 32 kDa) functions in the immune responses of various leukocytes. However, the role of neutrophil Bam32 in inflammation is entirely unknown. Here, we determined the role of Bam32 in chemokine CXCL2-induced neutrophil chemotaxis in three mouse models of neutrophil recruitment. By using intravital microscopy in the mouse cremaster muscle, we found that transmigrated neutrophil number, neutrophil chemotaxis velocity, and total neutrophil chemotaxis distance were increased in Bam32^−/− mice when compared with wild-type (WT) mice. In CXCL2-induced mouse peritonitis, the total emigrated neutrophils were increased in Bam32^−/− mice at 2 but not 4 h. The CXCL2-induced chemotaxis distance and migration velocity of isolated Bam32^−/− neutrophils in vitro were increased. We examined the activation of small GTPases Rac1, Rac2, and Rap1; the levels of phospho-Akt2 and total Akt2; and their crosstalk with Bam32 in neutrophils. The deficiency of Bam32 suppressed Rap1 activation without changing the activation of Rac1 and Rac2. The pharmacological inhibition of Rap1 by geranylgeranyltransferase I inhibitor (GGTI298) increased WT neutrophil chemotaxis. In addition, the deficiency of Bam32, as well as the inhibition of Rap1 activation, increased the levels of CXCL2-induced Akt1/2 phosphorylation at Thr308/309 in neutrophils. The inhibition of Akt by SH-5 attenuated CXCL2-induced adhesion and emigration in Bam32^−/− mice. Together, our results reveal that Bam32 has a suppressive role in chemokine-induced neutrophil chemotaxis by regulating Rap1 activation and that this role of Bam32 in chemokine-induced neutrophil recruitment relies on the activation of PI3K effector Akt.     

Chikusetsu Saponin V Attenuates MPP+-Induced Neurotoxicity in SH-SY5Y Cells via Regulation of Sirt1/Mn-SOD and GRP78/Caspase-12 Pathways

Studies have shown that saponins from Panax japonicus (SPJ) possess neuroprotective effects. However, whether Chikusetsu saponin V (CsV), the most abundant member of SPJ, can exert neuroprotective effects against 1-methyl-4-phenylpyridinium ion (MPP⁺)-induced cytotoxicity is not known. In this study, we aimed to investigate the neuroprotective effects of CsV on MPP⁺-induced cytotoxicity in human neuroblastoma SH-SY5Y cells and explore its possible mechanisms. Our results show that CsV attenuates MPP⁺-induced cytotoxicity, inhibits ROS accumulation, and increases mitochondrial membrane potential dose-dependently. We also found that levels of Sirt1 protein and Mn-SOD mRNA significantly decreased in MPP⁺-treated group but were restored with CsV treatment in a dose-dependent manner. Furthermore, GRP78 protein and Caspase-12 mRNA levels were elevated by MPP⁺ exposure but reversed by CsV treatment. CsV inhibited the MPP⁺-induced downregulation of Bcl-2 and up-regulation of Bax in a dose-dependent manner and, thus, increased the ratio of Bcl-2/Bax. Overall, these results suggest that Sirt1/Mn-SOD and GRP78/Caspase-12 pathways might be involved in the CsV-mediated neuroprotective effects.     

Accumulation of Cytochrome b558 at the Plasma Membrane: Hallmark of Oxidative Stress in Phagocytic Cells

Neutrophils play a very key role in the human immune defense against pathogenic infections. The predominant players in this role during the activation of neutrophils are the release of cytotoxic agents stored in the granules and secretory vesicles and the massive production of reactive oxygen species (ROS) initiated by the enzyme NADPH oxidase. In addition, in living organisms, cells are continuously exposed to endogenous (inflammations, elevated neutrophil presence in the vicinity) and exogenous ROS at low and moderate levels (travels by plane, radiotherapy, space irradiation, blood banking, etc.). To study these effects, we used ROS induced by gamma radiation from low (0.2 Gy) to high (25 Gy) dose levels on PLB-985 cells from a myeloid cell line differentiated to neutrophil-like cells that are considered a good alternative to neutrophils. We determined a much longer lifetime of PLB-985 cells than that of neutrophils, which, as expected, decreased by increasing the irradiation dose. In the absence of any secondary stimulus, a very low production of ROS is detected with no significant difference between irradiated and non-irradiated cells. However, in phagocytosing cells, irradiation doses above 2 Gy enhanced oxidative burst in PLB-985 cells. Whatever the irradiation dose, NADPH oxidase devoid of its cytosolic regulatory units is observed at the plasma membrane in irradiated PLB-985 cells. This result is different from that observed for irradiated neutrophils in which irradiation also induced a translocation of regulatory subunits suggesting that the signal transduction mechanism or pathway operate differently in both cells.     

Rat neutrophil function,and leukotriene generation in essential fatty acid deficiency

Since the essential fatty acid linoleic acid is the precursor of arachidonic acid and thus of leukotriene B₄ (LTB₄), essential fatty acid deficiency (EFAD) may result in decreased synthesis of this stimulator of neutrophil granulocyte functions. Peritoneal and blood neutrophils from rats fed a diet with only 0.3% of energy requirements as linoleic acid and exhibiting biochemical evidence of EFAD showed substantial functional impairments compared to neutrophils from rats maintained on a diet with 3% of the energy requirement as linoleic acid. Oxidative burst activation (assessed by chemiluminescence), chemotaxis and aggregation were impaired upon stimulation with formylpeptides or the ionophore A23187. In contrast, these functions were intact on stimulation with exogenous LTB₄. Chemiluminescence was slightly but not significantly enhanced in EFAD rat neutrophils compared to controls when stimulated with phorbol myristate acetate (PMA). There were no differences between EFAD and control peritoneal neutrophils in the number of f-metleu-phe (fMLP) receptors, or in their affinity for the ligand, assessed with fML(³H)P. The fraction of responding cells also were similar, assessed with dichlorofluorescein diacetate fluorescence. Moreover, the endogenous LTB₄ production in response to A23187 or fMLP was decreased by 57.7% and 63.5%, respectively, in EFAD peritoneal neutrophils. Thus, EFAD was associated with reductions of LTB₄ production and neutrophil responsiveness to A23187 and formylpeptides but not to LTB₄ or PMA, which supports the hypothesis that endogenous LTB₄ may contribute to the activation of neutrophil functions involved in inflammation and host defense.     

Copper Transfer from Cu–Aβ to Human Serum Albumin Inhibits Aggregation,Radical Production and Reduces Aβ Toxicity

Amyloid‐β peptides (Aβ) and the protein human serum albumin (HSA) interact in vivo. They are both localised in the blood plasma and in the cerebrospinal fluid. Among other functions, HSA is involved in the transport of the essential metal copper. Complexes between Aβ and copper ions have been proposed to be an aberrant interaction implicated in the development of Alzheimer's disease, where Cu is involved in Aβ aggregation and production of reactive oxygen species (ROS). In the present work, we studied copper‐exchange reaction between Aβ and HSA or the tetrapeptide DAHK (N‐terminal Cu‐binding domain of HSA) and the consequence of this exchange on Aβ‐induced ROS production and cell toxicity. The following results were obtained: 1) HSA and DAHK removed Cu^II from Aβ rapidly and stoichiometrically, 2) HSA and DAHK were able to decrease Cu‐induced aggregation of Aβ, 3) HSA and DAHK suppressed the catalytic HO^. production in vitro and ROS production in neuroblastoma cells generated by Cu–Aβ and ascorbate, 4) HSA and DAHK were able to rescue these cells from the toxicity of Cu–Aβ with ascorbate, 5) DAHK was more potent in ROS suppression and restoration of neuroblastoma cell viability than HSA, in correlation with an easier reduction of Cu^II–HSA than Cu–DAHK by ascorbate, in vitro. Our data suggest that HSA is able to decrease aberrant Cu^II–Aβ interaction. The repercussion of the competition between HSA and Aβ to bind Cu in the blood and brain and its relation to Alzheimer's disease are discussed.