Increased atherosclerosis and vascular inflammation in APP transgenic mice with apolipoprotein E deficiency

• Published in: Atherosclerosis Vol. 210; no. 1; pp. 78 - 87
• Main Authors: Tibolla, G, Norata, G.D, Meda, C, Arnaboldi, L, Uboldi, P, Piazza, F, Ferrarese, C, Corsini, A, Maggi, A, Vegeto, E, Catapano, A.L
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ireland Ltd 01.05.2010; Elsevier
• Subjects: Amyloid beta-Peptides - analysis; Amyloid beta-Protein Precursor - analysis; Amyloid β protein; Animals; Aorta - pathology; Aortic Diseases - pathology; Apolipoprotein E; Apolipoproteins E - deficiency; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - pathology; Biological and medical sciences; Blood and lymphatic vessels; Brain Chemistry; Cardiology. Vascular system; Cardiovascular; Cholestenones - analysis; Cholesterol - analysis; Cholesterol - blood; Coronary heart disease; Enzyme-Linked Immunosorbent Assay; Female; Gene Expression; Heart; Immunohistochemistry; Inflammation; Intercellular Adhesion Molecule-1 - analysis; Interleukin-6 - analysis; Lipids - blood; Lipoproteins - blood; Male; Medical sciences; Mice; Mice, Transgenic; Reverse Transcriptase Polymerase Chain Reaction; Vascular inflammation; Amyloid β protein; Apolipoprotein E; Vascular inflammation; Deficiency; Rodentia; Cardiovascular disease; Inflammation; Vascular disease; Vertebrata; Mammalia; Mouse; β Amyloid protein; Animal; Atherosclerosis
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2009.10.040

Abstract Objective Atherosclerosis is associated with Alzheimer's disease (AD) in humans, but the nature of this link is still elusive. Aim of this study was to investigate aortic atherosclerosis development in a mouse model with central nervous system (CNS) restricted β-amyloid precursor protein (APP) overexpression. Methods and results APP23 mice, overexpressing the Swedish mutated human APP selectively in the brain, were crossed with mice lacking apolipoprotein E (ApoE KO). Nine weeks old mice were fed a western type diet for eight weeks, then atherosclerotic lesions, aortic wall and cortical tissues gene expression and β-amyloid (Aβ) deposition were evaluated. Compared with ApoE KO, APP23/ApoE KO mice developed larger aortic atherosclerotic lesions and showed significantly increased expression of MCP-1, IL-6, ICAM-1 and MTPase 6, a marker of oxidative stress in the vascular wall. Of note brain limited APP synthesis was associated with an increased microglia and brain endothelial cells activation, in spite of the absence of β-amyloid deposits in the brain or alteration in the levels of oxidized metabolites of cholesterol such as 4-cholesten-3-one. Conclusion Our study suggests that the vascular pro-inflammatory effects of CNS-localised APP overexpression lead to atherogenesis before parenchymal Aβ deposition and neuronal dysfunction.