journal article·2024-05-04Open access

Effects of Amyloid Beta (Aβ) Oligomers on Blood–Brain Barrier Using a 3D Microfluidic Vasculature-on-a-Chip Model

Samuel Chidiebere Uzoechi, Boyce Edwin Collins, Cody Joseph Badeaux, Yan Li, Sang Su Kwak, Doo Yeon Kim, Daniel Todd Laskowitz, Jin-Moo Lee, Yeoheung Yun

Applied Sciences· Volume 14· Issue 9

Abstract

The disruption of the blood–brain barrier (BBB) in Alzheimer’s Disease (AD) is largely influenced by amyloid beta (Aβ). In this study, we developed a high-throughput microfluidic BBB model devoid of a physical membrane, featuring endothelial cells interacting with an extracellular matrix (ECM). This paper focuses on the impact of varying concentrations of Aβ1–42 oligomers on BBB dysfunction by treating them in the luminal. Our findings reveal a pronounced accumulation of Aβ1–42 oligomers at the BBB, resulting in the disruption of tight junctions and subsequent leakage evidenced by a barrier integrity assay. Additionally, cytotoxicity assessments indicate a concentration-dependent increase in cell death in response to Aβ1–42 oligomers (LC50 ~ 1 µM). This study underscores the utility of our membrane-free vascular chip in elucidating the dysfunction induced by Aβ with respect to the BBB.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Barrier Structure and Function Studies · Alzheimer's disease research and treatments · Neurological Disease Mechanisms and Treatments

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Chemical, Biological, and Bioengineering, North Carolina Agricultural and Technical State University, Greensboro, NC 27411, USA

Department of Biomedical Engineering, Federal University of Technology, PMB 1526, Owerri 460114, Nigeria

Chemical & Biomedical Engineering, College of Engineering, Florida State University, Tallahassee, FL 32310, USA

Genetics and Aging Research Unit, Mass General Hospital, Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA

Neurosurgery, Anesthesiology & Neurobiology, Duke University Medical Center, Durham, NC 27710, USA

Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA

Funding

National Science Foundation · Cure Alzheimer’s Fund · National Institutes of Health

References (45)

Show source-provided references
1. The Blood-Brain Barrier10.1111/j.1469-8749.1961.tb10430.x ↗
2. Liu, L., Koo, Y., Akwitti, C., Russell, T., Gay, E., Laskowitz, D.T., and Yun, Y. (2019). Three-dimensional (3D) brain microphysiological system for organophosphates and neurochemical agent toxicity screening. PLoS ONE, 14.10.1371/journal.pone.0224657 ↗
3. Structure and function of the blood-brain barrier10.1016/j.nbd.2009.07.030 ↗
4. Morphogens and blood-brain barrier function in health and disease10.1080/21688370.2015.1090524 ↗
5. Drug transport across the blood-brain barrier10.1038/jcbfm.2012.126 ↗
6. Alzheimer’s disease and the amyloid-β peptide10.3233/JAD-2010-1221 ↗
7. Aβ1–42 oligomer-induced leakage in an in vitro blood-brain barrier model is associated with up-regulation of RAGE and metalloproteinases, and down-regulation of tight junction scaffold proteins10.1111/jnc.13122 ↗
8. Vascular contributions to cognitive impairment and dementia (VCID): A report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop10.1002/alz.12157 ↗
9. Cerebral amyloid angiopathy: A systematic review10.3988/jcn.2011.7.1.1 ↗
10. Bilodeau, P.A., Dickson, J.R., and Kozberg, M.G. (2024). The Impact of Anti-Amyloid Immunotherapies on Stroke Care. J. Clin. Med., 13.10.3390/jcm13051245 ↗
11. The potential mechanisms of A beta-receptor for advanced glycation end-products interaction disrupting tight junctions of the blood-brain barrier in Alzheimer’s disease10.3109/00207454.2013.825258 ↗
12. Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future10.1038/s41392-023-01484-7 ↗
13. MMP-Mediated Disruption of Claudin-5 in the Blood–Brain Barrier of Rat Brain After Cerebral Ischemia10.1007/978-1-61779-185-7_24 ↗
14. Modeling ischemic stroke in a triculture neurovascular unit on-a-chip10.1186/s12987-021-00294-9 ↗
15. Development and characterisation of a rat brain capillary endothelial culture: Towards an in vitro blood-brain barrier10.1242/jcs.103.1.23 ↗
16. Growth of brain microvessel endothelial cells on collagen gels: Applications to the study of blood-brain barrier physiology and CNS inflammation10.1007/BF02631256 ↗
17. Cell-Culture Models of the Blood–Brain Barrier10.1161/STROKEAHA.114.005427 ↗
18. In Vitro Blood-Brain Barrier Models-An Overview of Established Models and New Microfluidic Approaches10.1002/jps.24329 ↗
19. Li, Y., Li, D., Zhao, P., Nandakumar, K., Wang, L., and Song, Y. (2020). Microfluidics-based systems in diagnosis of Alzheimer’s disease and biomimetic modeling. Micromachines, 11.10.3390/mi11090787 ↗
20. SyM-BBB: A microfluidic blood brain barrier model10.1039/c2lc41208j ↗
21. Three-dimensional (3D) tetra-culture brain on chip platform for organophosphate toxicity screening10.1038/s41598-018-20876-2 ↗
22. Russell, T., Dirar, Q., Li, Y., Chiang, C., Laskowitz, D.T., and Yun, Y. (2023). Cortical Spheroid on Perfusable Microvascular Network in a Microfluidic Device. PLoS ONE, 18.10.1371/journal.pone.0288025 ↗
23. A perfused human blood-brain barrier on-a-chip for high-throughput assessment of barrier function and antibody transport10.1186/s12987-018-0108-3 ↗
24. In vitro grafting of hepatic spheroids and organoids on a microfluidic vascular bed10.1007/s10456-022-09842-9 ↗
25. In vitro characterization of conditions for amyloid-β peptide oligomerization and fibrillogenesis10.1074/jbc.M210207200 ↗
26. Preparation of oligomeric β-amyloid1–42 and induction of synaptic plasticity impairment on hippocampal slices
27. Quantify permeability using on-a-chip models in high-throughput applications10.1016/j.xpro.2023.102051 ↗
28. High throughput transepithelial electrical resistance (TEER) measurements on perfused membrane-free epithelia10.1039/D0LC00770F ↗
29. Liu, L., Koo, Y., Russell, T., Gay, E., Li, Y., and Yun, Y. (2020). Three-dimensional brain-on-chip model using human iPSC-derived GABAergic neurons and astrocytes: Butyrylcholinesterase posttreatment for acute malathion exposure. PLoS ONE, 15.10.1371/journal.pone.0230335 ↗
30. The role of human umbilical vein endothelial cells in osteogenic differentiation of dental follicle-derived stem cells in in vitro co-cultures10.7150/ijms.27318 ↗
31. Endothelial cells in culture: A model for studying vascular functions10.1006/phrs.1999.0655 ↗
32. Medina-Leyte, D.J., Domínguez-Pérez, M., Mercado, I., Villarreal-Molina, M.T., and Jacobo-Albavera, L. (2020). Use of Human Umbilical Vein Endothelial Cells (HUVEC) as a Model to Study Cardiovascular Disease: A Review. Appl. Sci., 10.10.3390/app10030938 ↗
33. Endothelial Barrier Integrity Is Disrupted In Vitro by Heme and by Serum From Sickle Cell Disease Patients10.3389/fimmu.2020.535147 ↗
34. Bartosova, M., Ridinger, D., Marinovic, I., Heigwer, J., Zhang, C., Levai, E., Westhoff, J.H., Schaefer, F., Terjung, S., and Hildenbrand, G. (2021). An experimental workflow for studying barrier integrity, permeability, and tight junction composition and localization in a single endothelial cell monolayer: Proof of concept. Int. J. Mol. Sci., 22.10.3390/ijms22158178 ↗
35. Ultrastructural features of the blood-brain barrier in biopsy tissue from Alzheimer’s disease patients10.1007/s004010050386 ↗
36. Amyloid β-peptide1–42 alters tight junction protein distribution and expression in brain microvessel endothelial cells10.1016/j.neulet.2006.03.047 ↗
37. Endothelial leakiness elicited by amyloid protein aggregation10.1038/s41467-024-44814-1 ↗
38. Tarafdar, A., Wolska, N., Krisp, C., Schlüter, H., and Pula, G. (2022). The amyloid peptide β disrupts intercellular junctions and increases endothelial permeability in a NADPH oxidase 1-dependent manner. Redox Biol., 52.10.1016/j.redox.2022.102287 ↗
39. Evolving functions of endothelial cells in inflammation10.1038/nri2171 ↗
40. Take, Y., Chikai, Y., Shimamori, K., Kuragano, M., Kurita, H., and Tokuraku, K. (2021). Amyloid β aggregation induces human brain microvascular endothelial cell death with abnormal actin organization. Biochem. Biophys. Rep., 29.10.1016/j.bbrep.2021.101189 ↗
41. The blood-brain barrier in Alzheimer’s disease10.1016/j.nbd.2016.07.007 ↗
42. Therapeutic modulation of cerebral microhemorrhage in a mouse model of cerebral amyloid angiopathy10.1161/STROKEAHA.111.626655 ↗
43. Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy10.1161/STROKEAHA.111.627562 ↗
44. Amyloid β peptide-induced inhibition of endothelial nitric oxide production involves oxidative stress-mediated constitutive eNOS/HSP90 interaction and disruption of agonist-mediated Akt activation10.1186/s12974-015-0304-x ↗
45. Shulyatnikova, T., and Hayden, M.R. (2023). Why Are Perivascular Spaces Important?. Medicina, 59.10.3390/medicina59050917 ↗