Blood-Brain Barrier Disruption Increases Amyloid-Related Pathology in TgSwDI Mice

Abstract

In Alzheimer’s disease (AD), several studies have reported blood-brain barrier (BBB) breakdown with compromised function. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are transport proteins localized at the BBB luminal membrane and play an important role in the clearance of amyloid-β (Aβ). The purpose of this study was to investigate the effect of pharmacological inhibition of Aβ efflux transporters on BBB function and Aβ accumulation and related pathology. Recently, we have developed an in vitro high-throughput screening assay to screen for compounds that modulate the integrity of a cell-based BBB model, which identified elacridar as a disruptor of the monolayer integrity. Elacridar, an investigational compound known for its P-gp and BCRP inhibitory effect and widely used in cancer research. Therefore, it was used as a model compound for further evaluation in a mouse model of AD, namely TgSwDI. TgSwDI mouse is also used as a model for cerebral amyloid angiopathy (CAA). Results showed that P-gp and BCRP inhibition by elacridar disrupted the BBB integrity as measured by increased IgG extravasation and reduced expression of tight junction proteins, increased amyloid deposition due to P-gp, and BCRP downregulation and receptor for advanced glycation end products (RAGE) upregulation, increased CAA and astrogliosis. Further studies revealed the effect was mediated by activation of NF-κB pathway. In conclusion, results suggest that BBB disruption by inhibiting P-gp and BCRP exacerbates AD pathology in a mouse model of AD, and indicate that therapeutic drugs that inhibit P-gp and BCRP could increase the risk for AD.

Perphenazine and prochlorperazine decrease glioblastoma U‑87 MG cell migration and invasion: Analysis of the ABCB1 and ABCG2 transporters, E‑cadherin, α‑tubulin and integrins (α3, α5, and β1) levels

“…4), and suggested NF-κB pathway as a potential mechanism for BBB disruption. Data from the in vivo studies showed downregulation of P-gp and BCRP, and upregulation of the receptor for advanced glycation end products (RAGE), which accompanied activation of NF-κB pathway in mouse brains (40). Our study has confirmed that elacridar impairs P-gp and BCRP levels.…”

Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

“…To prevent Aβ deposition and circumvent the toxic effects, various Aβ-scavenger pathways work together in the brain, including BBB transportation, extracellular degradation by Aβ-proteolytic enzymes, cellular uptake, intracellular degradation, interstitial fluid (ISF) bulk flow, and CSF absorption ( Ma et al, 2018 ; Abdallah et al, 2021 ). Studies have shown that 50% of Aβ is transported into the blood across the BBB by LRP-mediated transcytosis and degradation of Aβ in vascular smooth-muscle cells ( Tanzi et al, 2004 ).…”

Transporter Regulation in Critical Protective Barriers: Focus on Brain and Placenta

“…The Aβ42-mediated reduction of P-gp has been linked to NF-κB-signaling in the murine bEnd.3 cell model [ 63 ]. Changes in NF-κB-signaling have also been observed when treating TgSwDI mice with the dual-transporter inhibitor elacridar (BCRP and P-gp inhibitor) to reduce BBB efflux capacity, leading to a further increase in hippocampal Aβ-load and a reduction in P-gp abundance [ 64 ]. For Aβ40 treatments, changes in P-gp protein amount were linked to the transporter’s ubiquitination mediated by NEDD4-1, which, due to proteosomal degradation, reduces P-gp surface density [ 65 , 66 , 67 ].…”