Tags

Type your tag names separated by a space and hit enter

Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist.
J Alzheimers Dis. 2014; 41(2):535-49.JA

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+Show Affiliations

Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.Department of Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24643138

Citation

Fitz, Nicholas F., et al. "Improvement of Memory Deficits and Amyloid-β Clearance in Aged APP23 Mice Treated With a Combination of Anti-amyloid-β Antibody and LXR Agonist." Journal of Alzheimer's Disease : JAD, vol. 41, no. 2, 2014, pp. 535-49.
Fitz NF, Castranio EL, Carter AY, et al. Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist. J Alzheimers Dis. 2014;41(2):535-49.
Fitz, N. F., Castranio, E. L., Carter, A. Y., Kodali, R., Lefterov, I., & Koldamova, R. (2014). Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist. Journal of Alzheimer's Disease : JAD, 41(2), 535-49. https://doi.org/10.3233/JAD-132789
Fitz NF, et al. Improvement of Memory Deficits and Amyloid-β Clearance in Aged APP23 Mice Treated With a Combination of Anti-amyloid-β Antibody and LXR Agonist. J Alzheimers Dis. 2014;41(2):535-49. PubMed PMID: 24643138.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Improvement of memory deficits and amyloid-β clearance in aged APP23 mice treated with a combination of anti-amyloid-β antibody and LXR agonist. AU - Fitz,Nicholas F, AU - Castranio,Emilie L, AU - Carter,Alexis Y, AU - Kodali,Ravindra, AU - Lefterov,Iliya, AU - Koldamova,Radosveta, PY - 2014/3/20/entrez PY - 2014/3/20/pubmed PY - 2015/2/11/medline KW - APP23 mice KW - Abca1 KW - ApoE lipidation KW - LXR agonist KW - amyloid plaques KW - amyloid-β immunization KW - fear conditioning KW - interstitial fluid KW - microdialysis KW - radial water maze SP - 535 EP - 49 JF - Journal of Alzheimer's disease : JAD JO - J. Alzheimers Dis. VL - 41 IS - 2 N2 - 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. SN - 1875-8908 UR - https://www.unboundmedicine.com/medline/citation/24643138/Improvement_of_memory_deficits_and_amyloid_β_clearance_in_aged_APP23_mice_treated_with_a_combination_of_anti_amyloid_β_antibody_and_LXR_agonist_ L2 - https://content.iospress.com/openurl?genre=article&id=doi:10.3233/JAD-132789 DB - PRIME DP - Unbound Medicine ER -