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

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 beta-amyloid precursor protein (APP) overexpression. 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 beta-amyloid (Abeta) 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 beta-amyloid deposits in the brain or alteration in the levels of oxidized metabolites of cholesterol such as 4-cholesten-3-one. Our study suggests that the vascular pro-inflammatory effects of CNS-localised APP overexpression lead to atherogenesis before parenchymal Abeta deposition and neuronal dysfunction.