Year: 2023
Type: dissertation
Abstract: Polymorphism in APOE gene is the strongest genetic risk factor Alzheimer's disease. APOE has 3 allelic variants with different risk profiles for the disease- APOE2 is the protective allele, APOE3 is the risk allele and APOE4 is the harmful allele. ApoE4 isoform of the protein is known to be crucial for amyloid plaque pathology in AD, along with playing role in neuroinflammation, endolysosomal dysfunction, tau pathology, blood brain barrier dysfunction and impaired myelination. ApoE's main contributing effect for the disease is modulation of plaque pathology with ApoE4 accelerating the formation of plaques, by directly promoting Aβ fibrillization or hampering clearance of Aβ. On the other hand, ApoE2's protective effect on amyloid pathology is not yet clear. Moreover, while ApoE is expressed primarily by astrocytes in the brain, microglia also upregulate ApoE in the amyloid plaque niche. There is still debate regarding the celltype source of ApoE responsible for modulation of amyloid plaque formation. But recent evidence suggests that absence of ApoE in microglia do not affect amyloid pathology. Since astrocytes are the sole source of ApoE in the early stages of the disease, suggesting it is crucial for the amyloid plaque formation. There is also mounting evidence for a direct contribution of astrocytes to neuroinflammatory and neurodegenerative processes causing Alzheimer's disease. Therefore, we focussed on studying the role of astrocytes and astrocyte-derived ApoE in amyloid pathology in AD. To overcome the limitations of studying stem cell-derived human astrocytes in culture, we developed a chimeric AD model by transplanting human induced pluripotent stem cell (hiPSC)-derived astrocyte progenitors into neonatal mouse brains. Xenografted hiPSC-derived astrocyte progenitors differentiated into astrocytes that integrated functionally within the mouse host brain and matured in a cell-autonomous way retaining human-specific morphologies, unique features, and physiological properties. In Alzheimer´s chimeric brains, transplanted hiPSC-derived astrocytes responded to the presence of amyloid plaques undergoing morphological changes that seemed independent of the APOE allelic background. Due to limitations in studying transcriptomic changes in transplanted astrocytes in this model, we focused on mouse astrocytes carrying different APOE alleles. We generated this new model by knocking out endogenous mouse Apoe and then expressing different ApoE isoforms specifically in astrocytes using Adeno-associated virus (AAV) mediated expression in AppNL-G-F x Apoe-/- mice. Using this model, we showed that, compared to ApoE3, both ApoE4 and ApoE2 from astrocytes increase fibrillar plaque deposition. This effect of astrocyte-derived ApoE is largely cell autonomous as the plaques are formed even in the absence of microglia. We also show that microglia lacking endogenous ApoE are still able to mount a response to the amyloid plaques, which is modulated by the different astrocyte-derived ApoE isoforms. More importantly, we present transcriptomic changes in microglia, as well as astrocytes, identifying specific markers and pathways affected by astrocyte-derived ApoE isoforms. Overall, this thesis underlines the importance of astrocytes and astrocyte-derived ApoE in amyloid pathology in Alzheimer's disease.
Source: Lirias (KU Leuven)
Author: Preman, Pranav
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Awards: Dissecting the role of human astroglia in Alzheimer’s disease pathogenesis, Deciphering isogenic APOE isoform dependent neurodegenerative response in human glia, The role of protein aggregate maturation in Alzheimer's disease and other neurodegenerative disorders and its potential for disease monitoring and differential diagnosis., Dissecting the role of human astroglia in Alzheimer’s disease
OpenAlex ID: W6995462206