Authors: Vicario-Orri, Elena | Opazo, Carlos M. | Muñoz, Francisco J.
Article Type: Review Article
Abstract: Neurons communicate in the nervous system by carrying out information along the length of their axons to finally transmit it at the synapse. Proper function of axons and axon terminals relies on the transport of proteins, organelles, vesicles, and other elements from the site of synthesis in the cell body. Conversely, neurotrophins secreted from axonal targets and other components at nerve terminals need to travel toward the cell body for clearance. Molecular motors, namely kinesins and dyneins, are responsible for the movement of these elements along cytoskeletal tracks. Given the challenging structure of neurons, axonal transport machinery plays a crucial …role in maintaining neuronal viability and function, allowing the proper neurotransmitter release at the presynaptic ending. On this basis, failure of axonal transport has been proposed as a key player in the development and/or progression of neurodegenerative disorders such as Alzheimer's disease (AD). Increasing evidence suggests that amyloid-β peptide, a hallmark of AD, may disrupt axonal transport and in so doing, contribute to AD pathophysiology. Here we discuss the molecular mechanisms of axonal transport with specific emphasis on the possible relationship between defective axonal transport and AD. Show more
Keywords: Alzheimer's disease, amyloid-β peptide, axon, fast axonal transport, molecular motors
DOI: 10.3233/JAD-141080
Citation: Journal of Alzheimer's Disease, vol. 43, no. 4, pp. 1097-1113, 2015
Authors: Aso, Ester | Palomer, Ernest | Juvés, Salvador | Maldonado, Rafael | Muñoz, Francisco J. | Ferrer, Isidro
Article Type: Research Article
Abstract: The present study shows that chronic administration of the Cannabinoid receptor type 1 (CB1 ) receptor agonist arachidonyl-2-chloroethylamide (ACEA) at pre-symptomatic or at early symptomatic stages, at a non-amnesic dose, reduces the cognitive impairment observed in double AβPP(swe)/PS1(1dE9) transgenic mice from 6 months of age onwards. ACEA has no effect on amyloid-β (Aβ) production, aggregation, or clearance. However, ACEA reduces the cytotoxic effect of Aβ42 oligomers in primary cultures of cortical neurons, and reverses Aβ-induced dephosphorylation of glycogen synthase kinase-3β (GSK3β) in vitro and in vivo. Reduced activity of GSK3β in ACEA-treated mice is further supported by the reduced amount …of phospho-tau (Thr181) in neuritic processes around Aβ plaques. In addition, ACEA-treated mice show decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes when compared with age-matched vehicle-treated transgenic mice. Our present results show a beneficial effect of ACEA at both the neuronal, mediated at least in part by GSK3β inhibition, and glial levels, resulting in a reduction of reactive astrocytes and lower expression of interferon-γ. As a consequence, targeting the CB1 receptor could offer a versatile approach for the treatment of Alzheimer's disease. Show more
Keywords: Alzheimer's disease, astrogliosis, cannabinoid receptor, CB1 cognition, GSK3β, neuroprotection, transgenic mice
DOI: 10.3233/JAD-2012-111862
Citation: Journal of Alzheimer's Disease, vol. 30, no. 2, pp. 439-459, 2012
Authors: Ill-Raga, Gerard | Ramos-Fernández, Eva | Guix, Francesc X. | Tajes, Marta | Bosch-Morató, Mónica | Palomer, Ernest | Godoy, Juan | Belmar, Sebastián | Cerpa, Waldo | Simpkins, James W. | Inestrosa and, Nibaldo C. | Muñoz, Francisco J.
Article Type: Research Article
Abstract: Different mechanisms including oxidative stress are proposed for amyloid-β peptide (Aβ) neurotoxicity, and here we contribute to demonstrate that nitro-oxidative stress is playing a key role. Yeasts are a well-known model for H2 O2 toxicity. Interestingly, yeast cell wall prevents interaction of Aβ fibrils with membrane receptors or calcium channels and we found a significant viability reduction in yeasts when challenged with Aβ fibrils. Furthermore, iron and copper chelators, as well as the antioxidants glutathione and trolox, were neuroprotective on neuroblastoma cells and mouse hippocampal neurons challenged with Aβ fibrils. Glutathione prevents the oxidation, glycation and nitrotyrosination of cell proteins …induced by Aβ. Trolox protected neurons in cell viability studies, maintaining the vesicular transport integrity and preventing the trigger of apoptotic mechanisms. Interestingly, we have also found that brain derived neuronal factor (BDNF) and neurotrophin-3 (NT-3) were able to protect mouse hippocampal and cortical neurons against H2 O2 and Aβ fibrils. Considering that superoxide anion, produced by Aβ cell damage, and nitric oxide, whose production is altered in AD, react to form the highly reactive peroxynitrite anion, we studied the role of trolox to ameliorate the peroxynitrite cell damage. Finally, one of the major proteins to be nitrotyrosinated in AD, the triose phosphate isomerase (TPI) was assayed searching for a denitrase activity that could reverse intracellular nitrotyrosination. We have found that human neuroblastoma SH-SY5Y cells express a constitutive denitrase activity that partially denitrated nitro-TPI. Altogether, our results support a key role of nitro-oxidative stress in the neuronal damage induced by Aβ fibrils. Show more
Keywords: Alzheimer's disease, amyloid-β peptide, antioxidants, oxidative stress, peroxynitrite, triose phosphate isomerase
DOI: 10.3233/JAD-2010-100474
Citation: Journal of Alzheimer's Disease, vol. 22, no. 2, pp. 641-652, 2010
Authors: Ramos-Fernández, Eva | Tajes, Marta | Palomer, Ernest | ILL-Raga, Gerard | Bosch-Morató, Mònica | Guivernau, Biuse | Román-Dégano, Irene | Eraso-Pichot, Abel | Alcolea, Daniel | Fortea, Juan | Nuñez, Laura | Paez, Antonio | Alameda, Francesc | Fernández-Busquets, Xavier | Lleó, Alberto | Elosúa, Roberto | Boada, Mercé | Valverde, Miguel A. | Muñoz, Francisco J.
Article Type: Research Article
Abstract: Glycation and nitrotyrosination are pathological posttranslational modifications that make proteins prone to losing their physiological properties. Since both modifications are increased in Alzheimer's disease (AD) due to amyloid-β peptide (Aβ) accumulation, we have studied their effect on albumin, the most abundant protein in cerebrospinal fluid and blood. Brain and plasmatic levels of glycated and nitrated albumin were significantly higher in AD patients than in controls. In vitro turbidometry and electron microscopy analyses demonstrated that glycation and nitrotyrosination promote changes in albumin structure and biochemical properties. Glycated albumin was more resistant to proteolysis and less uptake by hepatoma cells occurred. Glycated …albumin also reduced the osmolarity expected for a solution containing native albumin. Both glycation and nitrotyrosination turned albumin cytotoxic in a cell type-dependent manner for cerebral and vascular cells. Finally, of particular relevance to AD, these modified albumins were significantly less effective in avoiding Aβ aggregation than native albumin. In summary, nitrotyrosination and especially glycation alter albumin structural and biochemical properties, and these modifications might contribute for the progression of AD. Show more
Keywords: Albumin, Alzheimer's disease, amyloid, glycation, nitrotyrosination, oxidative stress
DOI: 10.3233/JAD-130914
Citation: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 643-657, 2014
Authors: Tajes, Marta | Eraso-Pichot, Abel | Rubio-Moscardó, Fanny | Guivernau, Biuse | Ramos-Fernández, Eva | Bosch-Morató, Mònica | Guix, Francesc Xavier | Clarimón, Jordi | Miscione, Gian Pietro | Boada, Mercé | Gil-Gómez, Gabriel | Suzuki, Toshiharu | Molina, Henrik | Villà-Freixa, Jordi | Vicente, Rubén | Muñoz, Francisco J.
Article Type: Research Article
Abstract: Amyloid-β peptide (Aβ) aggregates induce nitro-oxidative stress, contributing to the characteristic neurodegeneration found in Alzheimer's disease (AD). One of the most strongly nitrotyrosinated proteins in AD is the triosephosphate isomerase (TPI) enzyme which regulates glycolytic flow, and its efficiency decreased when it is nitrotyrosinated. The main aims of this study were to analyze the impact of TPI nitrotyrosination on cell viability and to identify the mechanism behind this effect. In human neuroblastoma cells (SH-SY5Y), we evaluated the effects of Aβ42 oligomers on TPI nitrotyrosination. We found an increased production of methylglyoxal (MG), a toxic byproduct of the inefficient nitro-TPI function. …The proapoptotic effects of Aβ42 oligomers, such as decreasing the protective Bcl2 and increasing the proapoptotic caspase-3 and Bax, were prevented with a MG chelator. Moreover, we used a double mutant TPI (Y165F and Y209F) to mimic nitrosative modifications due to Aβ action. Neuroblastoma cells transfected with the double mutant TPI consistently triggered MG production and a decrease in cell viability due to apoptotic mechanisms. Our data show for the first time that MG is playing a key role in the neuronal death induced by Aβ oligomers. This occurs because of TPI nitrotyrosination, which affects both tyrosines associated with the catalytic center. Show more
Keywords: Alzheimer's disease, amyloid, apoptosis, methylglyoxal, 3-nitrotyrosine, triose-phosphate isomerase
DOI: 10.3233/JAD-131685
Citation: Journal of Alzheimer's Disease, vol. 41, no. 1, pp. 273-288, 2014