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

2021 ◽  
Vol 22 (3) ◽  
pp. 1231
Author(s):  
Ihab M. Abdallah ◽  
Kamal M. Al-Shami ◽  
Euitaek Yang ◽  
Amal Kaddoumi
Keyword(s):  
Mouse Model ◽  
Blood Brain Barrier ◽  
High Throughput Screening ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Amyloid Angiopathy ◽  
Cancer Resistance ◽  
Screening Assay ◽  
Blood Brain ◽  
High Throughput Screening Assay

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.

scholarly journals Monitoring Blood-Brain Barrier Integrity Following Amyloid-β Immunotherapy Using Gadolinium-Enhanced MRI in a PDAPP Mouse Model

2016 ◽  
Vol 54 (2) ◽  
pp. 723-735 ◽  
Author(s):  
Ines Blockx ◽  
Steve Einstein ◽  
Pieter-Jan Guns ◽  
Johan Van Audekerke ◽  
Caroline Guglielmetti ◽  
...  
Keyword(s):  
Mouse Model ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Barrier Integrity ◽  
Blood Brain ◽  
Enhanced Mri ◽  
Blood Brain Barrier Integrity

scholarly journals A Repurposing Approach Identifies Off-Patent Drugs with Fungicidal Cryptococcal Activity, a Common Structural Chemotype, and Pharmacological Properties Relevant to the Treatment of Cryptococcosis

2012 ◽  
Vol 12 (2) ◽  
pp. 278-287 ◽  
Author(s):  
Arielle Butts ◽  
Louis DiDone ◽  
Kristy Koselny ◽  
Bonnie K. Baxter ◽  
Yeissa Chabrier-Rosello ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Blood Brain Barrier ◽  
High Throughput Screening ◽  
Fungicidal Activity ◽  
Bioactive Molecules ◽  
Brain Barrier ◽  
Content Type ◽  
Blood Brain ◽  
Hydrophobic Moiety ◽  
High Throughput Screening Assay

ABSTRACT New, more accessible therapies for cryptococcosis represent an unmet clinical need of global importance. We took a repurposing approach to identify previously developed drugs with fungicidal activity toward Cryptococcus neoformans , using a high-throughput screening assay designed to detect drugs that directly kill fungi. From a set of 1,120 off-patent medications and bioactive molecules, we identified 31 drugs/molecules with fungicidal activity, including 15 drugs for which direct antifungal activity had not previously been reported. A significant portion of the drugs are orally bioavailable and cross the blood-brain barrier, features key to the development of a widely applicable anticryptococcal agent. Structural analysis of this set revealed a common chemotype consisting of a hydrophobic moiety linked to a basic amine, features that are common to drugs that cross the blood-brain barrier and access the phagolysosome, two important niches of C. neoformans . Consistent with their fungicidal activity, the set contains eight drugs that are either additive or synergistic in combination with fluconazole. Importantly, we identified two drugs, amiodarone and thioridazine, with activity against intraphagocytic C. neoformans . Finally, the set of drugs is also enriched for molecules that inhibit calmodulin, and we have confirmed that seven drugs directly bind C. neoformans calmodulin, providing a molecular target that may contribute to the mechanism of antifungal activity. Taken together, these studies provide a foundation for the optimization of the antifungal properties of a set of pharmacologically attractive scaffolds for the development of novel anticryptococcal therapies.

Passage of amyloid β protein antibody across the blood–brain barrier in a mouse model of Alzheimer’s disease

Peptides ◽  
2002 ◽  
Vol 23 (12) ◽  
pp. 2223-2226 ◽  
Author(s):  
William A. Banks ◽  
Brie Terrell ◽  
Susan A. Farr ◽  
Sandra M. Robinson ◽  
Naoko Nonaka ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Amyloid Β Protein ◽  
Blood Brain ◽  
Model Of Alzheimer’S Disease ◽  
Β Protein

Cerebral Amyloid Angiopathy and Blood-Brain Barrier Dysfunction

2020 ◽  
pp. 107385842095481
Author(s):  
Monica Gireud-Goss ◽  
Alexis F. Mack ◽  
Louise D. McCullough ◽  
Akihiko Urayama
Keyword(s):  
Blood Brain Barrier ◽  
Cerebral Amyloid Angiopathy ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Amyloid Angiopathy ◽  
Barrier Dysfunction ◽  
Vessel Occlusion ◽  
Main Hypothesis ◽  
Blood Brain ◽  
Cerebral Amyloid

Cerebral hemorrhage, a devastating subtype of stroke, is often caused by hypertension and cerebral amyloid angiopathy (CAA). Pathological evidence of CAA is detected in approximately half of all individuals over the age of 70 and is associated with cortical microinfarcts and cognitive impairment. The underlying pathophysiology of CAA is characterized by accumulation of pathogenic amyloid β (Aβ) fragments of amyloid precursor protein in the cerebral vasculature. Vascular deposition of Aβ damages the vessel wall, results in blood-brain barrier (BBB) leakiness, vessel occlusion or rupture, and leads to hemorrhages and decreased cerebral blood flow that negatively affects vessel integrity and cognitive function. Currently, the main hypothesis surrounding the mechanism of CAA pathogenesis is that there is an impaired clearance of Aβ peptides, which includes compromised perivascular drainage as well as dysfunction of BBB transport. Also, the immune response in CAA pathogenesis plays an important role. Therefore, the mechanism by which Aβ vascular deposition occurs is crucial for our understanding of CAA pathogenesis and for the development of potential therapeutic options.

scholarly journals Bisphenol A Inhibits the Transporter Function of the Blood-Brain Barrier by Directly Interacting with the ABC Transporter Breast Cancer Resistance Protein (BCRP)

2021 ◽  
Vol 22 (11) ◽  
pp. 5534
Author(s):  
Elin Engdahl ◽  
Maarten van Schijndel ◽  
Dimitrios Voulgaris ◽  
Michela Di Criscio ◽  
Kerry Ramsbottom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bisphenol A ◽  
Blood Brain Barrier ◽  
Breast Cancer Resistance Protein ◽  
Brain Barrier ◽  
Production Volume ◽  
Cancer Resistance ◽  
Blood Brain ◽  
Resistance Protein

The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA’s known impact on neurodevelopment.

scholarly journals Pharmacokinetics and Molecular Modeling Indicate nAChRα4-Derived Peptide HAEE Goes through the Blood–Brain Barrier

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 909
Author(s):  
Yurii A. Zolotarev ◽  
Vladimir A. Mitkevich ◽  
Stanislav I. Shram ◽  
Alexei A. Adzhubei ◽  
Anna P. Tolstova ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Laboratory Animals ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Bolus Administration ◽  
Blood Brain ◽  
The Brain

One of the treatment strategies for Alzheimer’s disease (AD) is based on the use of pharmacological agents capable of binding to beta-amyloid (Aβ) and blocking its aggregation in the brain. Previously, we found that intravenous administration of the synthetic tetrapeptide Acetyl-His-Ala-Glu-Glu-Amide (HAEE), which is an analogue of the 35–38 region of the α4 subunit of α4β2 nicotinic acetylcholine receptor and specifically binds to the 11–14 site of Aβ, reduced the development of cerebral amyloidogenesis in a mouse model of AD. In the current study on three types of laboratory animals, we determined the biodistribution and tissue localization patterns of HAEE peptide after single intravenous bolus administration. The pharmacokinetic parameters of HAEE were established using uniformly tritium-labeled HAEE. Pharmacokinetic data provided evidence that HAEE goes through the blood–brain barrier. Based on molecular modeling, a role of LRP1 in receptor-mediated transcytosis of HAEE was proposed. Altogether, the results obtained indicate that the anti-amyloid effect of HAEE, previously found in a mouse model of AD, most likely occurs due to its interaction with Aβ species directly in the brain.

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