PhD defence
3D modeling and RNA-based therapeutics for Dutch-type Cerebral amyloid angiopathy
- E. Daoutsali
- Date
- Thursday 21 September 2023
- Time
- Location
-
Academy Building
Rapenburg 73
2311 GJ Leiden
Supervisor(s)
- Prof. dr. W.M.C van Roon-Mom
- Prof.dr. A.A.M Aartsma-Rus
Summary
Dutch-type cerebral amyloid angiopathy (D-CAA) is a rare neurodegenerative/neurovascular disease caused by a point mutation in the amyloid precursor protein (APP) gene that leads to aggregation of the amyloid beta peptide in the brain vasculature. It is characterized by intracerebral hemorrhages, infarcts, cognitive decline and vascular dementia. To date there are no therapies that prevent or delay D-CAA onset or progression. In this thesis we aimed to model the disease using patient-derived cell models, develop and test an RNA-targeting therapy and look into the mutated protein trafficking in the cell. Using D-CAA patient-derived induced pluripotent stem cells as template, we generated state-of-the-art 3D brain organoids and successfully modeled the amyloid beta aggregation and other D-CAA disease signatures, also found in the D-CAA human brain. We developed and tested an RNA-targeting therapy that showed efficient and significant reduction of the amyloid beta peptide in D-CAA patient-derived cells and control mice. Finally, when looking into the mutated APP protein trafficking we have found that the Dutch mutation affects the processing and trafficking of APP protein prior to the generation of the amyloid beta fragment, a phenotype that was reversed when the RNA-targeting therapy was applied. With the data generated in this thesis we hope to further advance the knowledge on D-CAA disease mechanisms as well as the possibility for therapeutics that will benefit D-CAA patients.
PhD dissertations
Approximately one week after the defence, PhD dissertations by Leiden PhD students are available digitally through the Leiden Repository, that offers free access to these PhD dissertations. Please note that in some cases a dissertation may be under embargo temporarily and access to its full-text version will only be granted later.
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General information
Beadle's Office
pedel@bb.leidenuniv.nl
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