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,
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
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.