Josep Cladera
Autonomous University of Barcelona
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Featured researches published by Josep Cladera.
Biomacromolecules | 2011
Oxana Klementieva; Núria Benseny-Cases; Alejandro Gella; Dietmar Appelhans; Brigitte Voit; Josep Cladera
Dendrimers have been proved to interact with amyloids, although most of dendrimers assayed in amyloidogenic systems are toxic to cells. The development of glycodendrimers, poly(propyleneimine) (PPI) dendrimers decorated with maltose (Mal), represents the possibility of using dendrimers with a low intrinsic toxicity. In the present paper we show that fourth (PPI-G4-Mal) and fifth (PPI-G5-Mal) generation glycodendrimers have the capacity to interfere with Alzheimers amyloid peptide Aβ(1-40) fibrilization. The interaction is generation dependent: PPI-G5-Mal blocks amyloid fibril formation generating granular nonfibrillar amorphous aggregates, whereas PPI-G4-Mal generates clumped fibrils at low dendrimer-peptide ratios and amorphous aggregates at high ratios. Both PPI-G4-Mal and PPI-G5-Mal are nontoxic to PC12 and SH-SY5Y cells. PPI-G4-Mal reduces amyloid toxicity by clumping fibrils together, whereas amorphous aggregates are toxic to PC12 cells. The results show that glycodendrimers are promising nontoxic agents in the search for anti-amyloidogenic compounds. Fibril clumping may be an anti-amyloid toxicity strategy.
Molecular Pharmaceutics | 2012
Tomasz Wasiak; Maksim Ionov; Krzysztof Nieznanski; Hanna Nieznanska; Oxana Klementieva; Maritxell Granell; Josep Cladera; Jean-Pierre Majoral; Anne Marie Caminade; Barbara Klajnert
Alzheimers disease (AD) is characterized by pathological aggregation of β-amyloid peptides and MAP-Tau protein. β-Amyloid (Aβ) is a peptide responsible for extracellular Alzheimers plaque formation. Intracellular MAP-Tau aggregates appear as a result of hyperphosphorylation of this cytoskeletal protein. Small, oligomeric forms of Aβ are intermediate products that appear before the amyloid plaques are formed. These forms are believed to be most neurotoxic. Dendrimers are highly branched polymers, which may find an application in regulation of amyloid fibril formation. Several biophysical and biochemical methods, like circular dichroism (CD), fluorescence intensity of thioflavin T and thioflavin S, transmission electron microscopy, spectrofluorimetry (measuring quenching of intrinsic peptide fluorescence) and MTT-cytotoxicity assay, were applied to characterize interactions of cationic phosphorus-containing dendrimers of generation 3 and generation 4 (CPDG3, CPDG4) with the fragment of amyloid peptide (Aβ(1-28)) and MAP-Tau protein. We have demonstrated that CPDs are able to affect β-amyloid and MAP-Tau aggregation processes. A neuro-2a cell line (N2a) was used to test cytotoxicity of formed fibrils and intermediate products during the Aβ(1-28) aggregation. It has been shown that CPDs might have a beneficial effect by reducing the system toxicity. Presented results suggest that phosphorus dendrimers may be used in the future as agents regulating the fibrilization processes in Alzheimers disease.
Biochimica et Biophysica Acta | 2009
Marc Torrent; Daniel Sánchez; Víctor Buzón; M. Victòria Nogués; Josep Cladera; Ester Boix
Eosinophil cationic protein (ECP/RNase 3) and the skin derived ribonuclease 7 (RNase 7) are members of the RNase A superfamily. RNase 3 is mainly expressed in eosinophils whereas RNase 7 is primarily secreted by keratinocytes. Both proteins present a broad-spectrum antimicrobial activity and their bactericidal mechanism is dependent on their membrane destabilizing capacities. Using phospholipid vesicles as membrane models, we have characterized the protein membrane association process. Confocal microscopy experiments using giant unilamellar vesicles illustrate the morphological changes of the liposome population. By labelling both lipid bilayers and proteins we have monitored the kinetic of the process. The differential protein ability to release the liposome aqueous content was evaluated together with the micellation and aggregation processes. A distinct morphology of the protein/lipid aggregates was visualized by transmission electron microscopy and the proteins overall secondary structure in a lipid microenvironment was assessed by FTIR. Interestingly, for both RNases the membrane interaction events take place in a different behaviour and timing: RNase 3 triggers first the vesicle aggregation, while RNase 7 induces leakage well before the aggregation step. Their distinct mechanism of action at the membrane level may reflect different in vivo antipathogen functions.
New Journal of Chemistry | 2009
Barbara Klajnert; Michela Cangiotti; Sara Calici; Maksim Ionov; Jean-Pierre Majoral; Anne-Marie Caminade; Josep Cladera; Maria Bryszewska; Maria Francesca Ottaviani
Heparin is involved in the pathogenesis of prion diseases, affecting the process of fibril formation. It has been shown that whether it accelerates or inhibits fibrilogenesis depends on its concentration: prion peptide PrP 185-208 aggregates in the presence of 0.04 mg ml−1 heparin, but concentrations ten times lower or higher cause no aggregation. Polyamidoamine, polypropyleneimine and phosphorus dendrimers that previously exhibited anti-prion activity have been shown to interact with heparin. The interactions between cationic dendrimers and anionic heparin are mainly electrostatic. The present study shows that these interactions are indirectly responsible for the inhibition or enhancement of fibril formation by dendrimers.
Analytical Chemistry | 2014
Núria Benseny-Cases; Oxana Klementieva; Marine Cotte; Isidre Ferrer; Josep Cladera
Amyloid peptides are the main component of one of the characteristic pathological hallmarks of Alzheimers disease (AD): senile plaques. According to the amyloid cascade hypothesis, amyloid peptides may play a central role in the sequence of events that leads to neurodegeneration. However, there are other factors, such as oxidative stress, that may be crucial for the development of the disease. In the present paper, we show that it is possible, by using Fourier tranform infrared (FTIR) microscopy, to co-localize amyloid deposits and lipid peroxidation in tissue slides from patients affected by Alzheimers disease. Plaques and lipids can be analyzed in the same sample, making use of the characteristic infrared bands for peptide aggregation and lipid oxidation. The results show that, in samples from patients diagnosed with AD, the plaques and their immediate surroundings are always characterized by the presence of oxidized lipids. As for samples from non-AD individuals, those without amyloid plaques show a lower level of lipid oxidation than AD individuals. However, it is known that plaques can be detected in the brains of some non-AD individuals. Our results show that, in such cases, the lipid in the plaques and their surroundings display oxidation levels that are similar to those of tissues with no plaques. These results point to lipid oxidation as a possible key factor in the path that goes from showing the typical neurophatological hallmarks to suffering from dementia. In this process, the oxidative power of the amyloid peptide, possibly in the form of nonfibrillar aggregates, could play a central role.
Biomacromolecules | 2013
Oxana Klementieva; E. Aso; D. Filippini; Núria Benseny-Cases; M. Carmona; S. Juvés; Dietmar Appelhans; Josep Cladera; I. Ferrer
Poly(propylene imine) (PPI) glycodendrimers are promising candidates as drug carriers and antiamyloidogenic and antiprionic agents. In this study the anti-β-amyloid capacity of PPI glycodendrimers of the fourth and fifth generations was investigated in vitro and in vivo. We assessed distinct PPI glycodendrimers including G4mDS and G5mDS, with electroneutral maltose shell, and G4mOS and G4m-IIIOS, with cationic maltose or maltotriose shell. Our results show that in vitro PPI maltose dendrimers reduce the toxicity of Aβ(1-42). However, only the electroneutral maltose dendrimers G4mDS and G5mDS reduce the toxicity of Alzheimers disease brain extracts in SH-SY5Y neuroblastoma cells. PPI maltose dendrimers with electroneutral or cationic surface penetrate the cytoplasm of cultured cells, and they reach the brain when administered intranasally. Both cationic G4mOS and electroneutral G4mDS are able to modify the total burden of β-amyloid in APP/PS1 mice. The studied dendrimers did not reverse memory impairment in APP/PS1 mice following chronic administration; moreover, cationic G4mOS caused cognitive decline in nontransgenic mice. In spite of the capacity of G4mDS and G4mOS to cross the blood-brain barrier and modulate Aβ aggregation in APP/PS1 mice, further studies are needed to learn how to reduce the harmful effects of maltose dendrimers in vivo.
Biochimica et Biophysica Acta | 1988
Josep Cladera; Ma Luisa Galisteo; Mireia Dun˜ach; Pedro L. Mateo; Esteve Padrós
Abstract Spectrophotometric and microcalorimetric techniques have been used to study the influence of cations on the thermal denaturation of bacteriorhodopsin. Deionized (blue) membrane at pH 5.0 shows a lower enthalpy of denaturation than native purple membrane, as well as a denaturation temperature about 20C° lower. Divalent cation binding increases both the temperature and enthalpy of denaturation. pH values also affect thermal denaturation of deionized membrane. At pH 6.5, a denaturation temperature about 20C° higher than at pH 4.0 and a much higher enthalpy are obtained. Ultraviolet difference spectra suggest that tryptophan residues are located in more exposed regions in the deionized membrane than in the native membrane. Hg2+, which does not promote the purple form, only slightly affects the temperature and enthalpy of denaturation. The small reversible pretransition observed for native purple membrane at about 80°C, attributed to a disordering of the lattice distribution of bacteriorhodopsin molecules, is absent in the deionized membrane and in that supplemented either with 1 mol of Mn2+ or 5–20 Hg2+ mol per mol of bacteriorhodopsin. The possible contribution of surface membrane potential and of defined protein conformation to bacteriorhodopsin stability is discussed.
Journal of Bioenergetics and Biomembranes | 1996
Josep Cladera; Jean-Louis Rigaud; Hervé Bottin; Mireia Duñach
Photosystem I reaction center from the cyanobacteriumSynechocystis sp PCC6803 was reconstituted into phosphatidylcholine/phosphatidic acid liposomes. Liposomes prepared by reversephase evaporation were treated with various amounts of different detergents and protein incorporation was analyzed at each step of the solubilization process. After detergent removal the activities of the resulting proteoliposomes were measured. The most efficient reconstitution was obtained by insertion of the protein complex into preformed liposomes destabilized by saturating amounts of octylglucoside. In the presence of N-methylphenazonium methosulfate and ascorbic acid, liposomes containing the reaction center catalyzed a light-dependent net H+ uptake as measured by the 9-aminoacridine fluorescence quenching and the pH meter. An important benefit of the new reconstitution procedure is that it produces a homogeneous population of large-size proteoliposomes with a low ionic permeability and with a majority inwardly directed H+ transport activity. In optimal conditions, a light-induced δpH of about 1.8 units could be sustained at 20‡C in the presence of valinomycin. In the absence of valinomycin, a “back-pressure” effect of an electrical transmembrane potential decreased both the rate and the extent of the H+ transport. The reaction center was also co-reconstituted with F0F1 H+-ATPases from chloroplasts and from the thermophilic bacterium, PS3. The coreconstituted system was shown to catalyze a light-dependent phosphorylation which could only be measured in the presence of a high concentration of PSI (low lipid/PSI ratios) while no δpH could be detected.
Current Alzheimer Research | 2010
Xavier Fernàndez-Busquets; Jovita Ponce; Ramona Bravo; Muriel Arimon; Tania Martiañez; Alejandro Gella; Josep Cladera; Nuria Durany
One mechanism leading to neurodegeneration during Alzheimers disease (AD) is amyloid beta peptide (Abeta)-induced neurotoxicity. Among the factors proposed to potentiate Abeta toxicity is its covalent modification through carbohydrate-derived advanced glycation endproducts (AGEs). Other experimental evidence, though, indicates that certain polymeric carbohydrates like the glycosaminoglycan (GAG) chains found in proteoglycan molecules attenuate the neurotoxic effect of Abeta in primary neuronal cultures. Pretreatment of the 42-residue Abeta fragment (Abeta1-42) with the ubiquitous brain carbohydrates, glucose, fructose, and the GAG chondroitin sulfate B (CSB) inhibits Abeta1-42-induced apoptosis and reduces the peptide neurotoxicity on neuroblastoma cells, a cytoprotective effect that is partially reverted by AGE inhibitors such as pyridoxamine and L-carnosine. Thioflavin T fluorescence measurements indicate that at concentrations close to physiological, only CSB promotes the formation of Abeta amyloid fibril structure. Atomic force microscopy imaging and Western blot analysis suggest that glucose favours the formation of globular oligomeric structures derived from aggregated species. Our data suggest that at short times carbohydrates reduce Abeta1-42 toxicity through different mechanisms both dependent and independent of AGE formation.
Biochemical and Biophysical Research Communications | 2008
Marta Cortijo-Arellano; Jovita Ponce; Nuria Durany; Josep Cladera
Amyloid fibrils are a hallmark of Alzheimers and prion diseases. In both pathologies fibrils are found associated to glycosaminoglycans, modulators of the aggregation process. Amyloid peptides and proteins with very poor sequence homologies originate very similar aggregates. This implies the possible existence of a common formation mechanism. A homologous structural motif has recently been described for the Alzheimers peptide Abeta(1-28) and the prion protein fragment PrP(185-208). We have studied the influence histidine residues and heparin on the aggregation process of both peptides and determined the possible amyloid characteristics of PrP(185-208), still unknown. The results show that PrP(185-208) forms amyloid aggregates in the presence of heparin. Histidines influence the aggregation kinetics, as in Abeta(1-28), although to a lesser extent. Other spectroscopic properties of the PrP(185-208) fragment are shown to be equivalent to those of other amyloid peptides and PrP(185-208) is shown to be cytotoxic using a neuroblastoma cell line.