Type 2 Diabetes Aggravates Alzheimer's Disease-Associated Vascular Alterations of the Aorta in Mice

Article type: Research Article

Authors: Sena, Cristina M.^{a; b; *} | Pereira, Ana M.^{a; b} | Carvalho, Cristina^d | Fernandes, Rosa^b | Seiça, Raquel M.^{a; b} | Oliveira, Catarina R.^{c; d} | Moreira, Paula I.^{a; d; *}

Affiliations: [a] Institute of Physiology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [b] IBILI - Institute of Biomedical Imaging and Life Sciences, Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [c] Institute of Biochemistry, Faculty of Medicine, University of Coimbra, Coimbra, Portugal | [d] CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

Correspondence: [*] Correspondence to: Cristina M. Sena, Institute of Physiology, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal. E-mail: csena@ci.uc.pt and Paula I. Moreira, Institute of Physiology, Faculty of Medicine, University of Coimbra & Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal. E-mail: venta@ci.uc.pt/pimoreira@fmed.uc.pt.

Abstract: Vascular risk factors are associated with a higher incidence of dementia. In fact, diabetes mellitus is considered a main risk factor for Alzheimer's disease (AD) and both diseases are characterized by vascular dysfunction. However, the underlying mechanisms remain largely unknown. Here, the effects of high-sucrose-induced type 2 diabetes (T2D) in the aorta of wild type (WT) and triple-transgenic AD (3xTg-AD) mice were investigated. 3xTg-AD mice showed a significant decrease in body weight and an increase in postprandial glycemia, glycated hemoglobin (HbA1c), and vascular nitrotyrosine, superoxide anion (O2•−), receptor for the advanced glycation end products (RAGE) protein, and monocyte chemoattractant protein-1 (MCP-1) levels when compared to WT mice. High-sucrose intake caused a significant increase in body weight, postprandial glycemia, HbA1c, triglycerides, plasma vascular cell adhesion molecule 1 (VCAM-1), and vascular nitrotyrosine, O2•−, RAGE, and MCP-1 levels in both WT and 3xTg-AD mice when compared to the respective control group. Also, a significant decrease in nitric oxide-dependent vasorelaxation was observed in 3xTg-AD and sucrose-treated WT mice. In conclusion, AD and T2D promote similar vascular dysfunction of the aorta, this effect being associated with elevated oxidative and nitrosative stress and inflammation. Also, AD-associated vascular alterations are potentiated by T2D. These findings support the idea that metabolic alterations predispose to the onset and progression of dementia.

Keywords: Alzheimer's disease, aorta, endothelium, inflammation, oxidative stress, type 2 diabetes

DOI: 10.3233/JAD-141008

Journal: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 127-138, 2015