Authors: Guix, Francesc X. | Sartório, Carmem L. | ILL-Raga, Gerard
Article Type: Review Article
Abstract: Human life unfolds not only in time and space, but also in the recollection and interweaving of memories. Therefore, individual human identity depends fully on a proper access to the autobiographical memory. Such access is hindered under pathological conditions such as Alzheimer’s disease, which affects millions of people worldwide. Unfortunately, no effective cure exists to prevent this disorder, the impact of which will rise alarmingly within the next decades. While Alzheimer’s disease is largely considered to be the outcome of amyloid-β (Aβ) peptide accumulation in the brain, conceiving this complex disorder strictly as the result of Aβ-neurotoxicity is perhaps a …too straight-line simplification. Instead, complementary to this view, the tableau of molecular disarrangements in the Alzheimer’s disease brain may be reflecting, at least in part, a loss of function phenotype in memory processing. Here we take BACE1 translation and degradation as a gateway to study molecular mechanisms putatively involved in the transition between memory and neurodegeneration. BACE1 participates in the excision of Aβ-peptide from its precursor holoprotein, but plays a role in synaptic plasticity too. Its translation is governed by eIF2α phosphorylation: a hub integrating cellular responses to stress, but also a critical switch in memory consolidation. Paralleling these dualities, the eIF2α -kinase HRI has been shown to be a nitric oxide-dependent physiological activator of hippocampal BACE1 translation. Finally, beholding BACE1 as a representative protease active in the CNS, we venture a new perspective on the cellular basis of memory, which may incorporate neurodegeneration in itself as a drift in memory consolidating systems. Show more
Keywords: Alzheimer’s disease, β-secretase, eIF2α, exosomes, heme-regulated eIF-2α kinase, memory, nitric oxide, physiological stress response, proteolysis, translation initiation
DOI: 10.3233/ADR-180089
Citation: Journal of Alzheimer's Disease Reports, vol. 3, no. 1, pp. 113-148, 2019
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