D-4F decreases brain arteriole inflammation and improves cognitive performance in LDL receptor-null mice on a Western diet.
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-1alpha (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 alpha-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.
Buga
Georgette M
GM
Department of Medicine, David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, CA 90095-1679, USA. gbuga@mednet.ucla.edu
Frank
Joy S
JS
Mottino
Giuliano A
GA
Hendizadeh
Michael
M
Hakhamian
Ashkan
A
Tillisch
Jan H
JH
Reddy
Srinivasa T
ST
Navab
Mohamad
M
Anantharamaiah
G M
GM
Ignarro
Louis J
LJ
Fogelman
Alan M
AM
D000199:Actins; D000818:Animals; D016632:Apolipoprotein A-I / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects* / Q000473:pathology*; D001921:Brain / Q000098:blood supply* / Q000187:drug effects* / Q000473:pathology; D018932:Chemokine CCL2 / Q000235:genetics; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D003071:Cognition / Q000187:drug effects; D004032:Diet; D005260:Female; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000188:drug therapy; D007249:Inflammation / Q000188:drug therapy; D019402:Macrophage Inflammatory Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018697:Nootropic Agents / Q000494:pharmacology*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
D000199:Actins; D016632:Apolipoprotein A-I; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; C465468:D-4F peptide; D019402:Macrophage Inflammatory Proteins; D018697:Nootropic Agents; D011973:Receptors, LDL