期刊
JOURNAL OF ALZHEIMERS DISEASE
卷 41, 期 2, 页码 535-549出版社
IOS PRESS
DOI: 10.3233/JAD-132789
关键词
Abca1; ApoE lipidation; APP23 mice; amyloid-beta immunization; amyloid plaques; fear conditioning; interstitial fluid; LXR agonist; microdialysis; radial water maze
资金
- NIA NIH HHS [R01 AG037481, R01AG037919, R01AG037481, R01 AG037919] Funding Source: Medline
- NIEHS NIH HHS [R21 ES021243, R21ES021243] Funding Source: Medline
Passive amyloid-beta (A beta) vaccination has shown significant effects on amyloid pathology in pre-depositing amyloid-beta protein precursor (A beta PP) mice but the results in older mice are inconsistent. A therapeutic effect of LXR and RXR agonists consisting of improved memory deficits and A beta pathology has been demonstrated in different Alzheimer's disease (AD) mouse models. Here, we report the effect of a combination of N-terminal A beta 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 A beta 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 A beta 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 A beta levels, indicating an increased A beta 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-A beta treatments can ameliorate cognitive deficits in A beta PP mice with advanced AD-like phenotype in conjunction with a decrease of A beta in brain interstitium and increase of ApoE lipidation without affecting the existing amyloid plaques.
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