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.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]
Elacridar treatment for 48 and 72 h resulted in a concentration-dependent reduction in transendothelial electrical resistance (TEER) measurements where the monolayer tightness was disrupted by elacridar in the concentration range from 2.5–10 μM with treatment times of 48 and 72 h when compared to vehicle-treated cells (Figure 1A)
The reduction in TEER values was associated with a significant increase in the permeability of Lucifer yellow (LY) across the monolayer (Figure 1B), suggesting a leaky monolayer that is consistent with results observed with TEER measurements
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia [1,2]. It is considered the sixth leading cause of death among Americans above 65 years old. AD is characterized by the deposition and accumulation of amyloid-β (Aβ) in the brain parenchyma and cerebral vessels [3,4]. Aβ accumulation in the brain parenchyma forms senile plaques, whereas the extracellular deposition of Aβ in cerebral vessels forms cerebral amyloid angiopathy (CAA) [5,6]. Aβ peptides are derived from the proteolytic cleavage of the amyloid precursor protein (APP) to form Aβ40 and Aβ42. Aβ generated in the brain can be eliminated through transport proteins across the blood-brain barrier (BBB), enzymatic degradation, and perivascular drainage via the vascular basement membrane [7]
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