University of Cambridge
The Contribution of APP gene dosage to the molecular phenotypes of Alzheimer's disease in human trisomy 21 neurons
Abstract
dc:description.abstractDown syndrome is a condition caused by trisomy 21 and occurs in 1 out of 700 births. People with trisomy 21 are high risk for developing Alzheimer’s disease, a neurodegenerative disease that causes approximately 65% of dementia. People with trisomy 21 develop Alzheimer’s disease pathologies by age 30, and about 80% have dementia by the age of 65. Having three copies of the APP gene, which resides on Chr 21 is attributed to the incidence of Alzheimer’s disease in trisomy 21, supported by APP locus duplication which is fully penetrant for early onset familial Alzheimer's disease. However, not everyone with trisomy 21 develops clinical symptoms of Alzheimer's disease. In this thesis, human PSCs were differentiated into cortical neurons to study the cellular phenotypes associated with Alzheimer’s disease in vitro. To investigate the penetrance of the molecular phenotypes of Alzheimer’s disease pathologies, I reprogrammed dermal fibroblasts from six people with trisomy 21 into iPSC, which were differentiated into cortical neurons. I discovered that trisomy 21 neurons were fully penetrant for Alzheimer’s disease phenotypes, displaying altered APP processing and changes in tau biology. To study the contribution of increased APP dosage to AD-related phenotypes, CRISPR Cas9 was used to introduce out of frame mutations to disrupt the reading frame of mRNA in one copy of the APP gene, and I discovered that three functional copies of the APP gene are required to cause AD phenotypes in trisomy 21 neurons. I found that the extra copy of the APP gene contributed to enlarged early endosomes and impaired autophagic degradation, which I replicated by overexpressing APP T719F; a form of APP resistant to gamma-secretase cleavage. In summary, having three copies of chromosome 21 is causal and fully penetrant for AD-related phenotypes in vitro. In trisomy 21 neurons, APP dosage contributed to the molecular phenotypes of Alzheimer’s disease and the dysregulation of lysosomal degradation pathways, which provides a cellular mechanism for tau accumulation. These results signify an important role for APP in mediating Alzheimer’s disease progression in the context of trisomy 21.
Degree
thesis:*- Name dc:type.qualificationname
- Doctor of Philosophy (PhD)
- Level dc:type.qualificationlevel
- Doctoral
- Grantor dc:publisher.institution
- University of Cambridge
- Year dc:date.issued
- 2019
Author and committee
dc:creator, dc:contributor.*- Author dc:creator
-
- Momoh, Ayiba
- Advisor dc:contributor.advisor
-
- Livesey, Frederick
Subjects
dc:subject × 10Rights
dc:rightsIdentifiers
dc:identifier.*- DOI dc:identifier.doi
- https://doi.org/10.17863/CAM.41532
- OAI identifier oai:identifier
- oai:www.repository.cam.ac.uk:1810/294433