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 (A beta) reduces cerebral A beta 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 A beta plaques, A beta increases in blood vessels of treated patients. We hypothesize that an age-related decline in the mechanisms that clear A beta from the brain might be at least in part responsible for the failure to purge and re-distribute A beta. The expulsion of A beta 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 blood-brain barrier on the effectiveness of A beta 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 A beta 42. After behavioral testing animals were sacrificed at the age of 395 days (+/- 5 days) and antibody titres against A beta were measured. Brains were dissected and soluble/insoluble cerebral A beta 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 A beta 40 and A beta 42. Furthermore, immunization significantly reduced A beta plaque burden. In contrast, immunized APP/PS1+/-P-gp ko mice lacking functional P-gp did not show a reduction of A beta 40 or A beta 42 accumulation in the brain except for the soluble form of A beta 42. 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 A beta removal from the brain and increased intraparenchymal cerebral amyloid angiopathy after immunization against A beta. Our data indicate that the selective up-regulation of P-gp could enhance the efficacy of A beta immunization in the treatment or prevention of AD.