| First Author | Ding Y | Year | 2021 |
| Journal | Fluids Barriers CNS | Volume | 18 |
| Issue | 1 | Pages | 10 |
| PubMed ID | 33676539 | Mgi Jnum | J:348239 |
| Mgi Id | MGI:6728644 | Doi | 10.1186/s12987-021-00245-4 |
| Citation | Ding Y, et al. (2021) Protecting P-glycoprotein at the blood-brain barrier from degradation in an Alzheimer's disease mouse model. Fluids Barriers CNS 18(1):10 |
| abstractText | BACKGROUND: Failure to clear Abeta from the brain is partly responsible for Abeta brain accumulation in Alzheimer's disease (AD). A critical protein for clearing Abeta across the blood-brain barrier is the efflux transporter P-glycoprotein (P-gp). In AD, P-gp levels are reduced, which contributes to impaired Abeta brain clearance. However, the mechanism responsible for decreased P-gp levels is poorly understood and there are no strategies available to protect P-gp. We previously demonstrated in isolated brain capillaries ex vivo that human Abeta40 (hAbeta40) triggers P-gp degradation by activating the ubiquitin-proteasome pathway. In this pathway, hAbeta40 initiates P-gp ubiquitination, leading to internalization and proteasomal degradation of P-gp, which then results in decreased P-gp protein expression and transport activity levels. Here, we extend this line of research and present results from an in vivo study using a transgenic mouse model of AD (human amyloid precursor protein (hAPP)-overexpressing mice; Tg2576). METHODS: In our study, hAPP mice were treated with vehicle, nocodazole (NCZ, microtubule inhibitor to block P-gp internalization), or a combination of NCZ and the P-gp inhibitor cyclosporin A (CSA). We determined P-gp protein expression and transport activity levels in isolated mouse brain capillaries and Abeta levels in plasma and brain tissue. RESULTS: Treating hAPP mice with 5 mg/kg NCZ for 14 days increased P-gp levels to levels found in WT mice. Consistent with this, P-gp-mediated hAbeta42 transport in brain capillaries was increased in NCZ-treated hAPP mice compared to untreated hAPP mice. Importantly, NCZ treatment significantly lowered hAbeta40 and hAbeta42 brain levels in hAPP mice, whereas hAbeta40 and hAbeta42 levels in plasma remained unchanged. CONCLUSIONS: These findings provide in vivo evidence that microtubule inhibition maintains P-gp protein expression and transport activity levels, which in turn helps to lower hAbeta brain levels in hAPP mice. Thus, protecting P-gp at the blood-brain barrier may provide a novel therapeutic strategy for AD and other Abeta-based pathologies. |
