The APOE Pathway as a Modulator of Amyloid Pathology in Alzheimer's Disease Models

Abstract

Alzheimer’s disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) peptides and amyloid plaque deposition. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for sporadic AD, with apoE protein crucial for brain lipid transport. ATP-binding cassette subfamily A member 1 (ABCA1), another risk gene, loads lipids onto apoE, highlighting the importance of lipid homeostasis in AD. MicroRNA-33 regulates the expression of ABCA1 and apoE lipidation, although its effect on amyloid pathology is unknown. Additionally, apoE variants can modulate AD risk. The apoEε4R251G variant eliminates the increased risk associated with the APOEε4 allele. This variant is located within the lipid binding domain of apoE, however its roles in lipid homeostasis and amyloid pathology remain unexplored. This dissertation investigates the role of apoE in amyloid pathology. We first used microRNA-33 knockout mice within an amyloidosis mouse model to determine if increased ABCA1 and apoE lipidation affect amyloid pathology. We demonstrate that deleting microRNA-33 reduced Aβ levels and plaque deposition. Through our multi-omics approach, we identified that microRNA-33 regulates microglial function, and mechanistically confirmed in vitro that inhibition of microRNA-33 increased microglial migration and Aβ phagocytosis. We next explored if the astrocyte-specific deletion of microRNA-33 could similarly reduce amyloid pathology. While the loss of microRNA-33 in astrocytes increased ABCA1 levels, we did not observe an increase in apoE lipidation. Furthermore, the astrocyte-specific deletion of microRNA-33 did not reduce amyloid pathology to the extent seen in the whole-body knockouts, suggesting a critical role for microglial microRNA-33 or a synergistic effect across cell types. Finally, we investigated if the astrocytic expression of the novel R251G apoE variant modulated apoE lipid pathways and amyloid pathology in an amyloidosis mouse model. We show that apoEε4R251G exhibits increased lipid binding compared to apoEε4. Additionally, the R251G variant reduced levels of Aβ and plaque deposition. Furthermore, astrocytes expressing apoEε4R251G colocalized more around plaques compared to apoEε4 mice, suggesting that astrocytes might be influencing the changes observed in amyloid pathology. Collectively, our results highlight the role of apoE lipid homeostasis in AD and potential therapeutic targets that can modulate apoE function and mitigate amyloid pathology.