Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice.
High-fat diet and certain dietary patterns are associated with higher incidence of sporadic Alzheimer's disease (AD) and cognitive decline. However, no specific therapy has been suggested to ameliorate the negative effects of high fat/high cholesterol levels on cognition and amyloid pathology. Here we show that in 9-month-old APP23 mice, a high-fat/high-cholesterol (HF) diet provided for 4 months exacerbates the AD phenotype evaluated by behavioral, morphological, and biochemical assays. To examine the therapeutic potential of liver X receptor (LXR) ligands, APP23 mice were fed HF diet supplemented with synthetic LXR agonist T0901317 (T0). Our results demonstrate that LXR ligand treatment causes a significant reduction of memory deficits observed during both acquisition and retention phases of the Morris water maze. Moreover, the effects of T0 on cognition correlate with AD-like morphological and biochemical parameters. We found a significant decrease in amyloid plaque load, insoluble Abeta and soluble Abeta oligomers. In vitro experiments with primary glia demonstrate that Abca1 is essential for the proper lipidation of ApoE and mediates the effects of T0 on Abeta degradation by microglia. Microdialysis experiments performed on awake freely moving mice showed that T0 decreased Abeta levels in the interstitial fluid of the hippocampus, supporting the conclusion that this treatment increases Abeta clearance. The data presented conclusively shows that LXR activation in the context of a metabolic challenge has critical effects on AD phenotype progression by attenuating Abeta deposition and facilitating its clearance.
Fitz
Nicholas F
NF
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Cronican
Andrea
A
Pham
Tam
T
Fogg
Allison
A
Fauq
Abdul H
AH
Chapman
Robert
R
Lefterov
Iliya
I
Koldamova
Radosveta
R
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000627:therapeutic use*; D000071518:Liver X Receptors; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000209:etiology / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017551:Microdialysis; D017628:Microglia / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D010446:Peptide Fragments / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012153:Retention, Psychology / Q000187:drug effects; D013449:Sulfonamides / Q000627:therapeutic use*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D004041:Dietary Fats; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010446:Peptide Fragments; D012333:RNA, Messenger; D013449:Sulfonamides; C577836:ABCA1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C075222:amyloid beta-protein (1-42)