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Title Page 2

Abstract 5

Contents 7

Ⅰ. Introduction 10

1. Overview of blood-brain barrier function in CNS 10

1.1. BBB functions and physiology 10

1.2. Pathological mechanisms of BBB dysfunction 10

1.3. Cell-dependent effect on BBB dysfunction 11

2. Cell biology of transcytosis 11

2.1. Transcytosis; caveolae and clathrin 11

2.2. Caveolae mediated transcytosis 12

2.3. Mfsd2a-Cav1 interaction of transcytosis in BBB integrity 14

3. Hydrogen peroxide in disease modeling 15

4. Backgrounds and motivations; exploring BBB transcytosis in vitro 15

Ⅱ. Experimental methods and materials 16

1. Cell culture 16

2. Transwell BBB culture 16

3. H₂O₂ exposure 16

4. Transport assay 17

5. Immunofluorescence staining 17

6. Quantitative real-time PCR 18

7. Statistical analyses 18

Ⅲ. Results and discussion 19

1. Optimization of human BBB transwell tri-culture 19

2. Tri-cultured BMECs showed non-significant changes when exposed to ROS 21

3. Genes associated with caveolae-mediated transcytosis in BMECs were influenced by astrocytes and pericytes exposed to H₂O₂ 23

4. Damaged astrocytes and pericytes experience comparable DNA damage 25

5. Damaged astrocytes exhibit more severe secretory phenotype than pericytes 27

6. Oxidatively damaged astrocytes induces BSA transport across the BBB 29

7. CME remains unchanged during ROS-damaged cells co-cultured with BMECs 31

Ⅳ. Conclusion 33

1. Summary 33

2. Future perspectives 35

Ⅴ. References 37

List of Tables 8

Table 1. List of primer sequences used for qRT-PCR 18

List of Figures 8

Figure 1. Schematic representation of the transcytosis mechanism highlighting the clathrin and caveolae 12

Figure 2. TEM images comparing mouse endothelial cells (E) in the brain (left) and lung (right) 13

Figure 3. Schematic diagram of regulation of caveolae-mediated transcytosis via Mfsd2a-Cav1 interaction 14

Figure 4. Functional markers of human BMECs in tri-culture with human astrocytes and pericytes 20

Figure 5. Effect of 100 μM H₂O₂ exposure for 2 hours on the BBB tri-culture model of astrocytes, pericytes,... 22

Figure 6. Impact of ROS-damaged astrocytes and pericytes co-culture on Caveolin-1 and Mfsd2a... 24

Figure 7. ROS-induced DNA damage and cell cycle arrest in astrocytes and pericytes 26

Figure 8. Astrocytes exhibit a significant secretory phenotype, unlike pericytes 28

Figure 9. Oxidatively damaged astrocytes induce BSA transport across the BBB 30

Figure 10. CME remains unchanged during ROS-damaged cells co-cultured with BMECs 32

Figure 11. Schematic diagram illustrating the impact of damaged astrocytes and pericytes on caveolae-... 33

초록보기

 The blood-brain barrier(BBB), consisting of lining of by brain microvascular endothelial cells (BMECs) and surrounding astrocytes, and pericytes, is essential for brain homeostasis by restricting non-specific molecular transport into the brain. Dysfunction of the BBB is linked to neurological diseases, often preceding cognitive decline due to increased permeability. The barrier function of the BBB is primarily regulated by BMECs, which maintain tight junctions to limit the paracellular pathway and suppress transcytosis, while astrocytes and pericytes play critical roles in supporting these BBB functions. Therefore, damage to astrocytes or pericytes in pathological conditions can lead to changes in the BBB phenotype. While the loss of tight junctions in BBB breakdown is well-studied, the loss of control over transcytosis has not been fully explored. Recent studies have highlighted the importance of alterations in transcytosis during pathological conditions, emphasizing the need for further investigation for therapeutic strategies. Notably, an increase in caveolae-mediated transcytosis, which induces less specific molecular transport compared to clathrin-mediated transcytosis, has been observed.

This study investigates the role of astrocytes and pericytes in altering caveolae-mediated transcytosis under oxidative stress, a factor presents in many brain pathological conditions such as aging and ischemic stroke. To do this, I use a monoculture, dual-culture, and triple-culture of an in vitro human BBB model composed of a monolayer of BMECs, astrocytes, and pericytes. The results indicate that oxidative stress induced by hydrogen peroxide (H₂O₂) treatment increases caveolae-mediated transcytosis in BMECs, linked to the downregulation of Mfsd2a, an upstream regulator of Caveolin-1. Interestingly, oxidatively damaged astrocytes significantly increase the rate of caveolae-mediated transcytosis in the BBB, while pericytes exhibit protective effects. These findings provide valuable insights into developing therapeutic strategies to address non-specific molecular transport in the BBB in neurological diseases and to enhance drug delivery strategies targeting increased caveolae-mediated transcytosis.

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