The acyl-coenzyme A: cholesterol acyltransferase inhibitor CI-1011 reverses diffuse brain amyloid pathology in aged amyloid precursor protein transgenic mice.
Cerebral accumulation of amyloid-beta (Abeta) is characteristic of Alzheimer disease and of amyloid precursor protein (APP) transgenic mice. Here, we assessed the efficacy of CI-1011, an inhibitor of acyl-coenzyme A:cholesterol acyltransferase, which is suitable for clinical use, in reducing amyloid pathology in both young (6.5 months old) and aged (16 months old) human APP transgenic mice. Treatment of young animals with CI-1011 decreased amyloid plaque load in the cortex and hippocampus and reduced the levels of insoluble Abeta40 and Abeta42 and C-terminal fragments of APP in brain extracts. In aged mice, CI-1011 specifically reduced diffuse amyloid plaques with a minor effect on thioflavin S-positive dense-core plaques. Reduced diffusible amyloid was accompanied by suppression of astrogliosis and enhanced microglial activation. Collectively, these data suggest that CI-1011 treatment reduces amyloid burden in human APP mice by limiting generation and increasing clearance of diffusible Abeta.
Huttunen
Henri J
HJ
Neurobiology of Disease Laboratory, Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Havas
Daniel
D
Peach
Camilla
C
Barren
Cory
C
Duller
Stephan
S
Xia
Weiming
W
Frosch
Matthew P
MP
Hutter-Paier
Birgit
B
Windisch
Manfred
M
Kovacs
Dora M
DM
D000081:Acetamides; D000085:Acetates / Q000494:pharmacology* / Q000627:therapeutic use; D000375:Aging / Q000187:drug effects*; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000494:pharmacology* / Q000627:therapeutic use
D000081:Acetamides; D000085:Acetates; D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D053764:Presenilin-1; D011725:Pyridines; D013449:Sulfonamides; D013451:Sulfonic Acids; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C087132:CP 113818; C423185:avasimibe; D002784:Cholesterol; D002785:Sterol O-Acyltransferase