Sascha Bruckmann*, Anja Brenn, Markus Grube, Katharina Niedrig, Silva Holtfreter, Oliver von Bohlen und Halbach, Martin Groschup, Markus Keller and Silke Vogelgesang Pages 656 - 667 ( 12 )
Background: Immunization against beta-amyloid (Aβ) reduces cerebral Aβ deposits and improves cognitive capacities in transgenic mouse models, and thus has been considered a promising disease- modifying therapeutic approach for Alzheimer’s disease (AD). Although clinical trials in AD patients have yielded evidence for clearance of parenchymal Aβ plaques, Aβ increases in blood vessels of treated patients. We hypothesize that an age-related decline in the mechanisms that clear Aβ from the brain might be at least in part responsible for the failure to purge and re-distribute Aβ. The expulsion of Aβ via the blood-brain barrier is mediated by specialized transport proteins such as P-glycoprotein (P-gp, ABCB1/MDR1).Objective: The objective of this study is to investigate the influence of the absence of P-gp at the bloodbrain barrier on the effectiveness of Aβ peptide immunization in APP/PS1+/- P-gp ko mice. Methods: Male APP/PS1+/- P-gp wt (n = 8) and APP/PS1+/- P-gp ko (n = 8) mice were actively immunized with human Aβ42. After behavioral testing animals were sacrificed at the age of 395 days (+/- 5 days) and antibody titres against Aβ were measured. Brains were dissected and soluble/insoluble cerebral Aβ was quantified, additionally the number of amyloid plaques and severity of amyloid angiopathy were evaluated. Results: In immunized mice with intact P-gp, our results showed a significant reduction of soluble and insoluble Aβ40 and Aβ42. Furthermore, immunization significantly reduced Aβ plaque burden. In contrast, immunized APP/PS1+/- P-gp ko mice lacking functional P-gp did not show a reduction of Aβ40 or Aβ42 accumulation in the brain except for the soluble form of Aβ42. Furthermore, after active immunization these mice displayed a stronger intracerebral amyloid angiopathy. Conclusion: The results show that the absence of P-gp results in a significant disturbance of Aβ removal from the brain and increased intraparenchymal cerebral amyloid angiopathy after immunization against Aβ. Our data indicate that the selective up-regulation of P-gp could enhance the efficacy of Aβ immunization in the treatment or prevention of AD.
Active immunization, Alzheimer's disease, amyloid angiopathy, beta-amyloid, blood-brain-barrier, clearance, Pglycoprotein.
Department of Neuropathology, Institute of Pathology, University Medicine Greifswald, D-17487, Greifswald, Department of Neuropathology, Institute of Pathology, University Medicine Greifswald, Greifswald, Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald, Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Department of Immunology, University Medicine, Greifswald, Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Friedrich-Loeffler-Institute, Institute for Novel and Emerging Infectious Diseases, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Greifswald, Friedrich-Loeffler-Institute, Institute for Novel and Emerging Infectious Diseases, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Greifswald, Department of Neuropathology, Institute of Pathology, University Medicine Greifswald, Greifswald