Oral apolipoprotein A-I mimetic peptide improves cognitive function and reduces amyloid burden in a mouse model of Alzheimer's disease.
Recent evidence indicates that inflammation may significantly contribute to the pathogenesis of Alzheimer's disease (AD). Since the apo A-I mimetic peptide D-4F has been shown to inhibit atherosclerotic lesion formation and regress already existing lesions (in the presence of pravastatin) and the peptide also decreases brain arteriole inflammation, we undertook a study to evaluate the efficacy of oral D-4F co-administered with pravastatin on cognitive function and amyloid beta (A beta) burden in the hippocampus of APPSwe-PS1 Delta E9 mice. Three groups of male mice were administered D-4F and pravastatin, Scrambled D-4F (ScD-4F, a control peptide) and pravastatin in drinking water, while drinking water alone served as control. The escape latency in the Morris Water Maze test was significantly shorter for the D-4F+statin administered animals compared to the other two groups. While the hippocampal region of the brain was covered with 4.2+/-0.5 and 3.8+/-0.6% of A beta load in the control and ScD-4F+statin administered groups, in the D-4F+statin administered group A beta load was only 1.6+/-0.1%. Furthermore, there was a significant decrease in the number of activated microglia (p<0.05 vs the other two groups) and activated astrocytes (p<0.05 vs control) upon oral D-4F+statin treatment. Inflammatory markers TNFalpha and IL-1 beta levels were decreased significantly in the D-4F+statin group compared to the other two groups (for IL-1 beta p<0.01 vs the other two groups and for TNF-alpha p<0.001 vs control) and the expression of MCP-1 were also less in D-4F+statin administered group compared to the other two groups. These results suggest that the apo A-I mimetic peptide inhibits amyloid beta deposition and improves cognitive function via exerting anti-inflammatory properties in the brain.
Atherosclerosis Research Unit and Department of Medicine, University of Alabama at Birmingham Medical Center, Birmingham, AL-35294, USA. hande@uab.edu
Shaila P
SP
Handattu
David W
DW
Garber
Candyce E
CE
Monroe
Thomas
T
van Groen
Inga
I
Kadish
Gaurav
G
Nayyar
Dongfeng
D
Cao
Mayakonda N
MN
Palgunachari
Ling
L
Li
G M
GM
Anantharamaiah
D000284:Administration, Oral; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage; D016632:Apolipoprotein A-I / Q000008:administration & dosage*; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D058225:Plaque, Amyloid / Q000187:drug effects / Q000502:physiology; D017035:Pravastatin / Q000008:administration & dosage; D058255:Protease Nexins; D011956:Receptors, Cell Surface / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C465468:D-4F peptide; D053583:Interleukin-1beta; D058255:Protease Nexins; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; D002784:Cholesterol; D017035:Pravastatin