Dr. Cheryl Wellington & Dr. Haakon Nygaard
Project Title: Precision genetic model of neurovascular unit to study Alzheimer disease
Grant Name: 2019 CLEAR Operating Grant
Grant Duration: 2019-2021 (two years)
Research Lay Summary:
Although scientists realize that understanding how to keep blood vessels in the brain healthy may offer new ways to treat Alzheimer disease, a big challenge is that there are not many methods to study brain blood vessels that translate to human physiology. What has been developed is a method to grow functional three dimensional human blood vessels in the test tube using “tissue engineering” technology.
This research will use this technology to make brain blood vessels using Alzheimer disease patient cells. These disease-like vessels will be used to rapidly test questions about Alzheimer disease pathophysiology and assist in the development of therapeutics.
Final Report(s):
What do we know about dementia that we did not know before this project?
Vascular risk factors play a major role in clinical AD, but we do not know much about the mechanisms of these relationships other than using mouse models or traditional cellular models, both of which are poor mimics of the human neurovascular unit.
This project enabled us to learn much more about how to construct improved 3D multicellular models of the human neurovascular unit, and provided preliminary data about the importance of lipoproteins including apoE on neurovascular unit function.
Why is this knowledge important to the understanding of the cause(s), treatment(s) or cure(s) of Alzheimer disease and or related dementias?
Vascular risk factors such as high blood pressure or high cholesterol can be managed using existing drugs and epidemiological studies show AD risk is lowered when vascular factors are managed. However, we don’t know exactly how. Studies using human-based models are important because they will reveal the mechanisms.
The follow articles reference the advancements of this research:
Cameron T, Bennet T, Rowe EM, Anwer M, Wellington CL, Cheung KC. (2021). Review of Design Considerations for Brain-on-a-Chip Models. Micromachines. 12: 441.
Robert J, Button EB, Martin EM, McAlary L, Gidden Z, Gilmour, G Boyce G, Caffrey TM, Agbay A, Clark A, Silverman JM, Cashman NR, Wellington CL. (2020). Cerebrovascular amyloid angiopathy in bioengineered vessels is reduced by high-density lipoprotein particles enriched in Apolipoprotein E. Molecular Neurogeneration.
Jerome Robert, Nicholas L. Weilinger, Li-Ping Zao, Stefano Cataldi, Emily B. Button, Sophie Stukas, Emma M. Martin, Megan Gilmour, Tara M. Caffrey, Elyn M. Rowe, Matthew Farrer, Brian MacVicar, Cheryl L. Wellington. (2020). An in vitro bioengineered model of the human arterial neurovascular unit to study neurodegenerative disease. Molecular Neurodegeneration.
Robert J, Weilinger NL, Cao LP, Cataldi S, Button EB, Stukas S, Martin EM, Seibler P, Gilmour M, Caffrey TM, Rowe EM, Fan J, MacVicar B, Farrer MJ, Wellington CL. (2020). An in vitro bioengineered model of the human art.