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Understanding transport mechanisms across the human blood-brain barrier in Alzheimer's disease

Bell, Luisa. Understanding transport mechanisms across the human blood-brain barrier in Alzheimer's disease. 2024, Doctoral Thesis, University of Basel, Faculty of Science.

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Official URL: https://edoc.unibas.ch/96816/

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Abstract

Summary for a Lay Audience in English
The blood-brain barrier (BBB) is a critical guardian that controls what substances can pass
from the bloodstream into the brain. It is made up of specialized cells, the so-called brain
endothelial cells between blood and brain that form tight connections, allowing only certain
molecules like gases and small fat-soluble substances to pass through easily. Other essential
nutrients and larger molecules need special transport systems to get across. One of these
transport systems involves the transferrin receptor (TfR), which helps move iron into the brain.
Iron is vital for brain function, and the TfR ensures it gets where it needs to go. ApoE4 is a
genetic variant of the apolipoprotein E (ApoE) that significantly increases the risk of developing
Alzheimer's disease (AD). ApoE4 can make the BBB more permeable, meaning it becomes
leakier and less effective at protecting the brain. This can lead to various problems, including
disrupted transport of essential molecules and increased risk of brain damage.
To study how ApoE4 affects the BBB and to develop new treatments for AD, scientists use
different experimental models. These include lab-grown cells, animal models, and samples
from human patients. In my research, I used stem cells to create brain endothelial cells with
the ApoE4 genetic variant to investigate how this risk factor affects transport across the BBB
via the TfR. I found that ApoE4 changes the way membrane-bound compartments, called
endosomes, transport substances like transferrin, disrupting iron balance in the cells.
Besides working with single types of two-dimensional (2D) brain cells, I also explored advanced
models called complex in vitro models (CIVMs). These include organoids (miniature, simplified
versions of organs) and microphysiological systems, which mimic the human BBB more closely
than traditional methods, in three dimensions (3D). These models can provide valuable insights
into how diseases develop and how drugs can be designed to treat them. In my research, I
adapted and optimized tissue technologies and advanced digital tools from histopathology for
CIVMs, primarily using BBB organoids for preclinical safety tests. My work aims to increase
the translatability of the development of new treatments from non-clinical to clinical and
therefore increased the success of developing novel treatments e.g. for AD.
In summary, understanding and improving the BBB through advanced models is essential for
developing effective drugs for brain disorders like AD. These models help ensure that new
treatments are safe and effective before they reach clinical trials, ultimately benefiting patients.
Advisors:Stokar von Neuforn, Nadine
Committee Members:Odermatt, Alex and Engelhardt, Britta
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15587
Thesis status:Complete
Number of Pages:235
Language:English
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss155875
edoc DOI:
Last Modified:24 Jan 2025 05:30
Deposited On:23 Jan 2025 11:46

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