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.

BACKGROUND: Immunization against beta-amyloid (Aß) reduces cerebral Aß 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 Aß plaques, Aß increases in blood vessels of treated patients. We hypothesize that an age-related decline in the mechanisms that clear Aß from the brain might be at least in part responsible for the failure to purge and re-distribute Aß. The expulsion of Aß 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 Aß 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 Aß42. After behavioral testing animals were sacrificed at the age of 395 days (+/- 5 days) and antibody titres against Aß were measured. Brains were dissected and soluble/insoluble cerebral Aß 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 Aß40 and Aß42. Furthermore, immunization significantly reduced Aß plaque burden. In contrast, immunized APP/PS1+/- P-gp ko mice lacking functional P-gp did not show a reduction of Aß40 or Aß42 accumulation in the brain except for the soluble form of Aß42. 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 Aß removal from the brain and increased intraparenchymal cerebral amyloid angiopathy after immunization against Aß. Our data indicate that the selective up-regulation of P-gp could enhance the efficacy of Aß immunization in the treatment or prevention of AD.