title: Lack of P-glycoprotein Results in Impairment of Removal of Beta-Amyloid and Increased Intraparenchymal Cerebral Amyloid Angiopathy after Active Immunization in a Transgenic Mouse Model of Alzheimer's Disease.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Neuropathology, Institute of Pathology, University Medicine Greifswald, Greifswald. Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Bruckmann
authors.affiliation: Department of Neuropathology, Institute of Pathology, University Medicine Greifswald, Greifswald. Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Brenn
authors.affiliation: Department of Pharmacology, Center of Drug Absorption and Transport (C_DAT), University Medicine Greifswald, Greifswald. Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Grube
authors.affiliation: Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald. Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Niedrig
authors.affiliation: Department of Immunology, University Medicine, Greifswald. Germany.
authors.forename: Silva
authors.initials: S
authors.lastname: Holtfreter
authors.affiliation: Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald. Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen und Halbach
authors.affiliation: Friedrich-Loeffler-Institute, Institute for Novel and Emerging Infectious Diseases, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Greifswald. Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Groschup
authors.affiliation: Friedrich-Loeffler-Institute, Institute for Novel and Emerging Infectious Diseases, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Greifswald. Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Keller
authors.affiliation: Department of Neuropathology, Institute of Pathology, University Medicine Greifswald, Greifswald. Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Vogelgesang
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000235:genetics; D000544:Alzheimer Disease / Q000150:complications* / Q000276:immunology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000906:Antibodies / Q000097:blood; D016657:Cerebral Amyloid Angiopathy / Q000209:etiology*; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000502:physiology; D005620:Freund's Adjuvant / Q000633:toxicity; D006470:Hemorrhage / Q000209:etiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C075222:amyloid beta-protein (1-42); D005620:Freund's Adjuvant; C095122:multidrug resistance protein 3; C507084:Abcb1b protein, mouse
keywords: Active immunization; Alzheimer's disease; Pglycoprotein; amyloid angiopathy; beta-amyloid; blood-brain-barrier; clearance