Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis
For peripherally administered drugs to reach the central nervous system (CNS) and treat amyotrophic lateral sclerosis (ALS), they must cross the blood–brain barrier (BBB). As mounting evidence suggests that the ultrastructure of the BBB is altered in individuals with ALS and in animal models of ALS...
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MDPI AG
2022-12-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/14/12/2803 |
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| author | Yijun Pan Yoshiteru Kagawa Jiaqi Sun Bradley J. Turner Cheng Huang Anup D. Shah Ralf B. Schittenhelm Joseph A. Nicolazzo |
| author_facet | Yijun Pan Yoshiteru Kagawa Jiaqi Sun Bradley J. Turner Cheng Huang Anup D. Shah Ralf B. Schittenhelm Joseph A. Nicolazzo |
| author_sort | Yijun Pan |
| collection | DOAJ |
| description | For peripherally administered drugs to reach the central nervous system (CNS) and treat amyotrophic lateral sclerosis (ALS), they must cross the blood–brain barrier (BBB). As mounting evidence suggests that the ultrastructure of the BBB is altered in individuals with ALS and in animal models of ALS (e.g., SOD1<sup>G93A</sup> mice), we characterized BBB transporter expression and function in transgenic C9orf72 BAC (C9-BAC) mice expressing a hexanucleotide repeat expansion, the most common genetic cause of ALS. Using an in situ transcardiac brain perfusion technique, we identified a 1.4-fold increase in <sup>3</sup>H-2-deoxy-D-glucose transport across the BBB in C9-BAC transgenic (C9) mice, relative to wild-type (WT) mice, which was associated with a 1.3-fold increase in brain microvascular glucose transporter 1 expression, while other general BBB permeability processes (passive diffusion, efflux transporter function) remained unaffected. We also performed proteomic analysis on isolated brain microvascular endothelial cells, in which we noted a mild (14.3%) reduction in zonula occludens-1 abundance in C9 relative to WT mice. Functional enrichment analysis highlighted trends in changes to various BBB transporters and cellular metabolism. To our knowledge, this is the first study to demonstrate altered BBB function in a C9orf72 repeat expansion model of ALS, which has implications on how therapeutics may access the brain in this mouse model. |
| first_indexed | 2024-03-09T15:58:45Z |
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| id | doaj.art-ce792643f94e4e4a96edfc45439b2c0c |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-09T15:58:45Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-ce792643f94e4e4a96edfc45439b2c0c2023-11-24T17:22:18ZengMDPI AGPharmaceutics1999-49232022-12-011412280310.3390/pharmaceutics14122803Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral SclerosisYijun Pan0Yoshiteru Kagawa1Jiaqi Sun2Bradley J. Turner3Cheng Huang4Anup D. Shah5Ralf B. Schittenhelm6Joseph A. Nicolazzo7Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, AustraliaFlorey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, AustraliaMonash Proteomics & Metabolomics Facility, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaMonash Proteomics & Metabolomics Facility, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaMonash Proteomics & Metabolomics Facility, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaDrug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, AustraliaFor peripherally administered drugs to reach the central nervous system (CNS) and treat amyotrophic lateral sclerosis (ALS), they must cross the blood–brain barrier (BBB). As mounting evidence suggests that the ultrastructure of the BBB is altered in individuals with ALS and in animal models of ALS (e.g., SOD1<sup>G93A</sup> mice), we characterized BBB transporter expression and function in transgenic C9orf72 BAC (C9-BAC) mice expressing a hexanucleotide repeat expansion, the most common genetic cause of ALS. Using an in situ transcardiac brain perfusion technique, we identified a 1.4-fold increase in <sup>3</sup>H-2-deoxy-D-glucose transport across the BBB in C9-BAC transgenic (C9) mice, relative to wild-type (WT) mice, which was associated with a 1.3-fold increase in brain microvascular glucose transporter 1 expression, while other general BBB permeability processes (passive diffusion, efflux transporter function) remained unaffected. We also performed proteomic analysis on isolated brain microvascular endothelial cells, in which we noted a mild (14.3%) reduction in zonula occludens-1 abundance in C9 relative to WT mice. Functional enrichment analysis highlighted trends in changes to various BBB transporters and cellular metabolism. To our knowledge, this is the first study to demonstrate altered BBB function in a C9orf72 repeat expansion model of ALS, which has implications on how therapeutics may access the brain in this mouse model.https://www.mdpi.com/1999-4923/14/12/2803amyotrophic lateral sclerosisblood–brain barrierbrain microvascular endothelial cellsC9orf72 geneproteomics |
| spellingShingle | Yijun Pan Yoshiteru Kagawa Jiaqi Sun Bradley J. Turner Cheng Huang Anup D. Shah Ralf B. Schittenhelm Joseph A. Nicolazzo Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis Pharmaceutics amyotrophic lateral sclerosis blood–brain barrier brain microvascular endothelial cells C9orf72 gene proteomics |
| title | Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis |
| title_full | Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis |
| title_fullStr | Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis |
| title_full_unstemmed | Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis |
| title_short | Altered Blood–Brain Barrier Dynamics in the C9orf72 Hexanucleotide Repeat Expansion Mouse Model of Amyotrophic Lateral Sclerosis |
| title_sort | altered blood brain barrier dynamics in the c9orf72 hexanucleotide repeat expansion mouse model of amyotrophic lateral sclerosis |
| topic | amyotrophic lateral sclerosis blood–brain barrier brain microvascular endothelial cells C9orf72 gene proteomics |
| url | https://www.mdpi.com/1999-4923/14/12/2803 |
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