The role of APOE-mediated microglial response in Aβ and Tau pathologies

Abstract

Alzheimer’s disease (AD) affects 50 million worldwide, posing an economic burden of 1 trillion dollars per year. Despite the advent of the first approved diseasemodifying drugs, no therapy is yet sufficient to halt the disease course or provide clinically relevant impact. Brains of AD patients are characterized by the sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting the ATN axis. These histopathological hallmarks are invariably associated with neuroinflammation, in which microglia play a critical role. In this vein, microgliosis exerts an executive role in AD onset and progression. GWAS studies reveal that many disease-modifying risk genes are highly expressed by microglia, including APOE. Noteworthy, mounting clinical and pre-clinical evidence posits APOE as a prominent player in AD pathophysiology standing out as a promising therapeutic target. Nevertheless, despite recent breakthroughs in molecular mechanisms underlying APOE effect(s) in AD, further research is urgently needed to gain more insights into the selective contribution of APOE-mediated microglial response in single ATN pathologies. Thus, we pave the way for downstream analyses in combined ATN models to investigate APOE modulation in Aβ-induced Tau pathology (see Annex). In the present work, we have examined the role of ApoE in Aβ and Tau pathology separately in wellcharacterized murine pre-clinical models. We questioned whether ApoE deletion ameliorates these pathologies and assessed how microglia modulate their response based on ApoE expression/deletion. In Chapter 3, we demonstrated that ApoE deficiency increased Aβ burden but lowered dense-core Aβ plaques, resulting in a shift towards diffuse amyloid pathology. Additionally, we have shown that Aβ dense-core plaques in the presence of ApoE were associated with a higher microglial response and phagocytic activity compared to diffuse pathology in the absence of ApoE expression. Importantly, our scRNA-seq data revealed that ApoE deletion locked microglia into a homeostatic state, whereas ApoE expression facilitated microglial conversion towards DAM phenotypes. Strikingly, we report for the first time a major ApoE effect in the transition from homeostatic to reactive microglia. Furthermore, we identified a new microglial subset termed inactive microglia, which was enriched in ApoE deficient mice in the context of Aβ pathology. In Chapter 4, we show that ApoE expression increases pathological Tau concentrations, Tau aggregation, and phagocytic microglia response throughout the brain in a primary Tauopathy model. Most importantly, we demonstrate a protective effect of downregulation or inhibition of ApoE expression in halting Taumediated neurodegeneration. These findings support lowering ApoE expression as a strategy to decrease Tau pathology and downstream processes, while further validation in different pre-clinical models is warranted. Overall, our findings provide support for therapeutic avenues targeting specific microglial phenotypes together with lowering overall ApoE levels in the brain as promising treatments to tackle AD and primary Tauopathies.