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

Autor: Ihab M. Abdallah, Kamal M Al-Shami, Euitaek Yang, Amal Kaddoumi
Rok vydání: 2021
Předmět:
Male
Pathology
Abcg2
lcsh:Chemistry
Mice
Tetrahydroisoquinolines
ATP Binding Cassette Transporter
Subfamily G
Member 2
lcsh:QH301-705.5
CAA
Spectroscopy
P-glycoprotein
biology
Chemistry
NF-kappa B
Brain
General Medicine
Immunohistochemistry
Extravasation
Computer Science Applications
Astrogliosis
medicine.anatomical_structure
Matrix Metalloproteinase 9
breast cancer resistance protein
Cerebral amyloid angiopathy
Alzheimer’s disease
Signal Transduction
medicine.medical_specialty
Amyloid
Mice
Transgenic
amyloid-β
Blood–brain barrier
Article
Catalysis
Cell Line
Tight Junctions
Inorganic Chemistry
Downregulation and upregulation
Alzheimer Disease
medicine
Animals
ATP Binding Cassette Transporter
Subfamily B
Member 1
Physical and Theoretical Chemistry
Molecular Biology
Amyloid beta-Peptides
Organic Chemistry
blood-brain barrier
medicine.disease
Disease Models
Animal
lcsh:Biology (General)
lcsh:QD1-999
Astrocytes
Immunoglobulin G
Synapses
biology.protein
Acridines
Zdroj: International Journal of Molecular Sciences, Vol 22, Iss 1231, p 1231 (2021)
International Journal of Molecular Sciences
Volume 22
Issue 3
ISSN: 1422-0067
DOI: 10.3390/ijms22031231
Popis: In Alzheimer&rsquo
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-&beta
(A&beta
). The purpose of this study was to investigate the effect of pharmacological inhibition of A&beta
efflux transporters on BBB function and A&beta
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-&kappa
B 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.
Databáze: OpenAIRE
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