Modulating amyloid‐beta proteostasis in the brain of 5xFAD mice by selective expression of angiotensin converting enzyme in microglia

Abstract

AbstractBackgroundAlzheimer’s Disease (AD) is a common and progressive neurodegenerative disease characterized by abnormalities in amyloid‐beta (Ab) proteostasis in the brain. Abnormal cleavage of Ab and aggregation into extracellular amyloid‐containing plaques is widely believed to contribute to neuroinflammation, synapse loss and neurotoxicity in AD. Microglia are brain‐resident myeloid‐lineage cells that mediate synapse homeostasis and the immune response to Ab deposition in the brain, and many Genome‐Wide Association Studies (GWAS) have identified late‐onset AD (LOAD) risk‐associated genes that are primarily expressed in microglia, suggesting their important role in disease pathogenesis (Kunkle et al., 2019, Wightman et al. 2021). Identifying signaling pathways in microglia that modulate Ab proteostasis may provide important targets for disease therapy.MethodThe gene encoding for Angiotensin Converting Enzyme (ACE) has been identified as an AD risk‐associated gene (Kunkle et al., 2019, Wightman et al, 2021), and ACE modulates the function of myeloid‐lineage cells, such as neutrophils and macrophages. ACE expression in macrophages appears to modulate their ability to decrease Ab plaque load in the brain and reverse cognitive abnormalities in AD model mice. Here, we developed a novel mouse model to express ACE specifically in microglia (RACE). We mated RACE mice to 5xFAD mice and examined the role of ACE expression in microglia using molecular, physiologic and behavioral techniques. Single nucleus RNA sequencing (10x Genomics) and digital spatial profiling on tissues sections (Nanostring GeoMx) was used to identify gene expression modulated by ACE in microglia.ResultWe find that ACE expression in microglia in 5xFAD mice increases amyloid phagocytosis, reduces plaque burden, rescues synapse and neuron loss, enhances microglial recruitment to plaques, rescues learning and memory deficits, and modulates gene expression associated with injury and autophagy in plaque‐associated microglia. Single‐nucleus RNA sequencing, proteomic profiling, synaptic plasticity, and pharmacological studies are in process to interrogate the molecular basis of ACE function in microglia.ConclusionACE expression in microglia has the remarkable capacity to restore Ab proteostasis, rescue synapse and neuron loss, and learning and memory abnormalities in 5xFAD mice. Signaling pathways and gene expression modulated by ACE in microglia may be targets for novel disease therapy.