Dr. Alois Alzheimer observed more than amyloid beta plaques around and neurofibrillary tau tangles within neurons in the brains of his patients. He also documented non-neuronal glial cells, like astrocytes and microglia, laden with unusually high numbers of abnormally large lipid (fat) droplets. Lipid droplets are normal cellular structures that store naturally present and necessary fats, but in these diseased brains, both the number and size of these droplets were dramatically increased. This finding was largely overlooked as researchers focused on the larger neurons and disease-specific protein deposits. In recent years, however, genetic and functional evidence increasingly implicates lipid dysfunction in glial cells—particularly microglia—as a central contributor in Alzheimer’s disease (AD). Genetic studies have identified gene variants primarily expressed in glial cells that influence both Alzheimer’s risk and lipid metabolism, including variants of APOE, a protein that transports lipids, and PLCg2 (P522R), an enzyme that regulates microglial functions, including lipid metabolism. Meanwhile, functional research has confirmed that lipid overload impairs normal microglial housekeeping function in Alzheimer’s patients.
Given this evidence, many scientists hypothesize that the mechanism linking these genetic variants to AD risk involves disrupted microglial lipid metabolism. Microglia enter different immune states depending on the conditions of their environment. Under healthy, normal conditions, microglia in a homeostatic immune state act as housekeepers of the brain, clearing debris they encounter by engulfing it (phagocytosis) and then breaking it down (lysosomal digestion). Microglia then store lipids from this debris in lipid droplets for later use as an energy source. However, when microglia encounter an excess of lipids in their environment—such as myelin debris from nerve fiber damage or due to a high-fat diet—they interpret it as a sign of disease or damage and enter a proinflammatory immune state. In this state, microglia alter their clearance activity and signal to other cell types to rally their immune response as well. While this proinflammatory state is normally protective and temporary, overwhelming lipid loads or a failure to process lipids properly due to mutations of key proteins can unbalance the system so that inflammation persists rather than resolves. In these cases, lipids over-accumulate within microglia, creating persistent damage signals that trigger chronic inflammation. This prolonged inflammatory state becomes harmful, damaging healthy brain tissue rather than protecting it.
Dr. van der Kant originally theorized that APOE and PLCg2 variants alter AD risk by changing how microglia expressing these variants handle lipids when the cells are in their homeostatic (housekeeping) state. To his surprise, his lab’s preliminary results contradicted this. Human stem cell-derived microglia cell cultures carrying either protective (APOE2, PLCg2) or risk (APOE4) gene variants had, to some extent, similar lipid and gene expression profiles under baseline conditions regardless of which gene variant was present. Based on these observations, Dr. van der Kant now hypothesizes that the difference between protective and risk variants is how they affect microglial responses when the cells encounter excess lipids in their environment. In this hypothesis, microglia with protective variants clear lipids and return to a baseline, non-inflammatory state more quickly, while microglia with risk variants become locked into proinflammatory states that cause chronic neuroinflammation and cell death.
The lab proposed three aims to address this hypothesis. In the first aim, they are mapping the response of microglia carrying risk or protective gene variants to a challenge by each of four types of lipids to determine how fast microglia revert to a homeostatic immune state after each specific challenge. They will measure gene expression (transcriptomics), changes in lipids (lipidomics), and levels of proinflammatory cytokines to determine microglia states. In the second aim, they are focusing on a few time points from the first aim to describe in more detail the immune states of these cells, with a particular emphasis on comparing protective and risk variants. In the third aim, they are exploring how the microglial response to lipids impacts other brain cell types (astrocytes and neurons) and the development of amyloid-related pathologies.
