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Journal of Lipid Research, Vol. 47, 2148-2160, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet

Georgette M. Buga^1,*, Joy S. Frank^*, Giuliano A. Mottino^*, Michael Hendizadeh^*, Ashkan Hakhamian^*, Jan H. Tillisch^*, Srinivasa T. Reddy^*,, Mohamad Navab^*, G. M. Anantharamaiah, Louis J. Ignarro and Alan M. Fogelman^*

^* Department of Medicine, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, CA 90095-1679
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at the University of California–Los Angeles, Los Angeles, CA 90095-1679
The Atherosclerosis Research Unit, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294

Published, JLR Papers in Press, July 12, 2006.

¹ To whom correspondence should be addressed. e-mail: gbuga{at}mednet.ucla.edu

LDL receptor-null mice on a Western diet (WD) have inflammation in large arteries and endothelial dysfunction in small arteries, which are improved with the apolipoprotein A-I mimetic D-4F. The role of hyperlipidemia in causing inflammation of very small vessels such as brain arterioles has not previously been studied. A WD caused a marked increase in the percent of brain arterioles with associated macrophages (microglia) (P < 0.01), which was reduced by oral D-4F but not by scrambled D-4F (ScD-4F; P < 0.01). D-4F (but not ScD-4F) reduced the percent of brain arterioles associated with CCL3/macrophage inflammatory protein-1 (P < 0.01) and CCL2/monocyte chemoattractant protein-1 (P < 0.001). A WD increased (P < 0.001) brain arteriole wall thickness and smooth muscle -actin, which was reduced by D-4F but not by ScD-4F (P < 0.0001). There was no difference in plasma lipid levels, blood pressure, or arteriole lumen diameter with D-4F treatment. Cognitive performance in the T-maze continuous alternation task and in the Morris Water Maze was impaired by a WD and was significantly improved with D-4F but not ScD-4F (P < 0.05). We conclude that a WD induces brain arteriole inflammation and cognitive impairment that is ameliorated by oral D-4F without altering plasma lipids, blood pressure, or arteriole lumen size.

Supplementary key words hyperlipidemia • lipoproteins • apolipoprotein A-I mimetic peptides • arterioles • hyperlipidemia • brain function

Abbreviations: LDLR^–/–, LDL receptor-null; MCP-1, monocyte chemoattractant protein-1; MIP-1, macrophage inflammatory protein-1; MWM, Morris Water Maze; ScD-4F, scrambled D-4F; T-CAT, T-maze continuous alternation task; WD, Western diet

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