Posttranslational Nitro-Glycative Modifications of Albumin in Alzheimer's Disease: Implications in Cytotoxicity and Amyloid-β Peptide Aggregation

Article type: Research Article

Authors: Ramos-Fernández, Eva^a | Tajes, Marta^a | Palomer, Ernest^a | ILL-Raga, Gerard^a | Bosch-Morató, Mònica^a | Guivernau, Biuse^a | Román-Dégano, Irene^b | Eraso-Pichot, Abel^a | Alcolea, Daniel^c | Fortea, Juan^c | Nuñez, Laura^d | Paez, Antonio^d | Alameda, Francesc^e | Fernández-Busquets, Xavier^{f; g; h} | Lleó, Alberto^c | Elosúa, Roberto^b | Boada, Mercé^{i; j} | Valverde, Miguel A.^a | Muñoz, Francisco J.^a

Affiliations: [a] Laboratory of Molecular Physiology and Channelopaties, Department of Experimental and Health Sciences, Universitat Pompeu Fabra (UPF), Barcelona, Catalonia, Spain | [b] Group of Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute (IMIM), Barcelona, Catalonia, Spain | [c] Alzheimer Laboratory, Neurology Department, Hospital de la Santa Creu i Sant Pau, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain | [d] Instituto Grifols, Barcelona, Catalonia, Spain | [e] Servei d'Anatomia Patológica, Universitat Autónoma de Barcelona (UAB) Hospital del Mar Research Institute (IMIM), Barcelona, Catalonia, Spain | [f] Nanomalaria Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Catalonia, Spain | [g] Barcelona Centre for International Health Research (CRESIB, Hospital Clínic-Universitat de Barcelona), Barcelona, Catalonia, Spain | [h] Biomolecular Interactions Team, Nanoscience and Nanotechnology Institute (IN2UB), University of Barcelona, Barcelona, Catalonia, Spain | [i] Memory Clinic of Fundació ACE. Institut Catalá de Neurociències Aplicades, Barcelona, Catalonia, Spain | [j] Neurology Department, Hospital G. Universitari Vall d'Hebron, Barcelona, Catalonia, Spain

Correspondence: [*] Correspondence to: Dr. Francisco J. Muñoz, Laboratori de Fisiologia Molecular i Canalopaties, Universitat Pompeu Fabra, C/ Dr. Aiguader, 88, Barcelona 08003, Spain. Tel.: +34 93 316 08 52; Fax: +34 93 316 09 01; E-mail: [email protected].

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.

Keywords: Albumin, Alzheimer's disease, amyloid, glycation, nitrotyrosination, oxidative stress

DOI: 10.3233/JAD-130914

Journal: Journal of Alzheimer's Disease, vol. 40, no. 3, pp. 643-657, 2014