title: Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist.
abstract: Passive amyloid-β (Aβ) vaccination has shown significant effects on amyloid pathology in pre-depositing amyloid-β protein precursor (AβPP) mice but the results in older mice are inconsistent. A therapeutic effect of LXR and RXR agonists consisting of improved memory deficits and Aβ pathology has been demonstrated in different Alzheimer's disease (AD) mouse models. Here, we report the effect of a combination of N-terminal Aβ antibody and synthetic LXR agonist T0901317 (T0) on AD-like phenotype of APP23 mice. To examine the therapeutic potential of this combination, the treatment of mice started at 11 months of age, when amyloid phenotype in this model is fully developed, and continued for 50 days. We show that Aβ immunization with or without LXR agonist restored the performance of APP23 transgenic mice in two behavior paradigms without affecting the existing amyloid plaques. Importantly, we did not observe an increase of brain microhemorrhage which is considered a significant side effect of Aβ vaccination. Target engagement was confirmed by increased Abca1 and ApoE protein level as well as increased ApoE lipidation in soluble brain extract. In interstitial fluid obtained by microdialysis, we demonstrate that immunization and T0 significantly reduced Aβ levels, indicating an increased Aβ clearance. We found no interaction between the immunotherapy and T0, suggesting no synergism, at least with these doses. The results of our study demonstrate that anti-Aβ treatments can ameliorate cognitive deficits in AβPP mice with advanced AD-like phenotype in conjunction with a decrease of Aβ in brain interstitium and increase of ApoE lipidation without affecting the existing amyloid plaques.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Fitz
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Emilie L
authors.initials: EL
authors.lastname: Castranio
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Alexis Y
authors.initials: AY
authors.lastname: Carter
authors.affiliation: Department of Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Iliya
authors.initials: I
authors.lastname: Lefterov
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Radosveta
authors.initials: R
authors.lastname: Koldamova
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000544:Alzheimer Disease / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D058227:Amyloidogenic Proteins / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003131:Combined Modality Therapy; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D006845:Hydrocarbons, Fluorinated / Q000627:therapeutic use*; D007116:Immunization, Passive; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018697:Nootropic Agents / Q000627:therapeutic use; D011897:Random Allocation; D013449:Sulfonamides / Q000627:therapeutic use*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D058227:Amyloidogenic Proteins; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D006845:Hydrocarbons, Fluorinated; D018697:Nootropic Agents; D013449:Sulfonamides; C577833:Abca1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
keywords: APP23 mice; Abca1; ApoE lipidation; LXR agonist; amyloid plaques; amyloid-β immunization; fear conditioning; interstitial fluid; microdialysis; radial water maze