Date of Award
8-9-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Alzheimer’s disease (AD) is the major cause of dementia. An inherited form of AD (dominant inherited AD) starts much earlier in life, often in the fourth and fifth decade. A recent case report described an individual who was resistant to dominantly inherited AD caused by a PSEN1-E280A mutation and was a homozygous carrier of the APOE3 Christchurch (APOE3ch) variant. A clear separation between amyloid and tau pathology occurred in this unique AD case. However, whether APOE3ch contributed to the protective effect remains unclear. In this thesis, we generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-β (Aβ) plaque-depositing model. We injected AD-Tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, amyloid was reduced associated with enhanced microglial response around plaques. We found an increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to receptors. Therefore, APOE3ch influences the microglial response to Aβ plaques, which suppresses Aβ-induced tau seeding and spreading. The results reveal new possibilities to leverage APOE3ch-receptor interactions and target Aβ-induced tauopathy in addition to current anti-amyloid therapies for treating AD patients. Moreover, we developed a whole-genome CRISPR screen that revealed the whole regulatory map for receptor-mediated internalization of APOE by BV2 cells and discovered two unexpected receptors - EGFR and VEGFR. We further demonstrated the interaction between EGFR and APOE at the domain level by recombinant proteins. Utilizing EGFR+ A549 cells, we discovered a synergistic effect from APOE on EGFR signaling and cellular transportation. These results will lead to new studies on APOE-receptor interactions and their roles both in physiological and pathological conditions including AD.
Language
English (en)
Chair and Committee
David Holtzman
Committee Members
Marco Colonna; Albert Davis; Andrea Soranno; Michael Gross; Peng Yuan
Recommended Citation
Chen, Yun, "Elucidating the first protective mutation from inherited Alzheimer’s Disease - Apolipoprotein E3 Christchurch (APOE3ch) and insights into APOE ligand-receptor interactions" (2024). Arts & Sciences Electronic Theses and Dissertations. 3289.
https://openscholarship.wustl.edu/art_sci_etds/3289