Fig. 9

Proposed mechanism. Our current findings and our previously published data [24,25,26, 71] suggest that Aβ (1) activates the ubiquitin ligase NEDD4 [71], which (2) tags the transporter with ubiquitin [25, 26], a signal that leads to (3) internalization of P-gp followed [24] by (4) proteasomal degradation (present study). In this series of three independent in vivo studies, we showed that when we pharmacologically intervene by blocking (1) ubiquitination, (2) internalization, and (3) proteasomal degradation of P-gp we prevent P-gp loss at the blood–brain barrier, which in turn lowers Aβ brain levels in vivo [24, 26], as we show herein. Created with BioRender.com