iPSC Macrophages/microglia and genome-wide CRISPR/Cas9 screening to investigate lipid accumulation in the pathophysiology of Alzheimer's Disease

Background

Lipid accumulation in the cell cytoplasm of Alzheimer's brains was observed in the earliest descriptions of the disease. However, the vast majority of biomedical research in Alzheimer's disease (AD) has focused on the two gross histopathological targets of amyloid plaques and neurofibrillary tangles. The result of this research has been over 200 clinical trials focusing on these two targets that failed to generate an effective therapy. There are several reasons for this failure; among these are the poor understanding of the fundamental pathophysiology of Alzheimer's disease and the poor choice of disease models to more faithfully mimic the human cells most associated with AD pathology.

Recently, GWAS studies have identified lipid metabolism as an important pathway in Alzheimer's disease (Jansen et al., 2019), with GWAS hits, such as Trem2 and ApoE, involved in lipid sensing and processing, in addition to regulation of inflammatory processes. A greater understanding of lipid regulation, and in particular of neuroinflammation, would be fundamental to understanding the pathophysiology of AD. Macrophages and microglia containing accumulations of lipids upon inflammation have been described (Nadjar, 2018). Lipid droplets, consisting of neutral lipids such as triacylglycerols and diacylglycerols, have been associated with inflammation and cytokine storage, but also with homeostatic functions, such as storage of fatty acids that could support phagocytosis and proper mitochondria functioning.

All these studies strongly evidence that fatty acids can modulate microglial phagocytic activity. More studies are needed however to understand the mechanisms by which microglia interact with fatty acids and how they can shift microglia from one phenotype/function to another. Moreover, we still need to address the net outcome of these functional shifts for brain homeostasis, since depending on the context, increasing microglial phagocytosis might be beneficial (e.g....