Amyloid β Induces Lipid Droplet‐Mediated Microglial Dysfunction in Alzheimer’s Disease

Abstract

AbstractBackgroundSeveral microglia‐expressed genes have emerged as top risk variants for Alzheimer’s disease (AD) that are involved in lipid droplet (LD) formation and processing. Impaired microglial phagocytosis is one of the main proposed outcomes by which these AD‐risk genes may contribute to neurodegeneration, but the mechanisms translating genetic association to cellular dysfunction remain unknown. LD accumulation in aging (Nat Neurosci. 23(2),194‐208, 2020) appears to increase microglial inflammatory responses, while inflammatory challenges increase LD formation, thereby potentially setting up a feed‐forward injury that could contribute to the relentless progression in AD.MethodLD formation is dependent upon age and disease progression, and is more prominent in the hippocampus in brains from human patients and the AD mouse model 5xFAD. Despite variability in LD load between microglia from male versus female animals and between cells from different brain regions, LD‐laden microglia exhibited a deficit in amyloid‐beta (Aβ) phagocytosis evaluated using AβpH ‐ a human Aβ1‐42 analog that exhibits fluorescence upon lysosomal internalization (Chem Sci. 12, 10901‐10918, 2021). Extensive unbiased lipidomic and metabolomic profiling in microglia identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation.ResultWe show that microglia form LDs upon exposure to Aβ, and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. Mechanistically, Aβ alone is sufficient to induce LD formation in microglia and that this conversion requires a specific metabolic conversion of FFAs to TAGs (the building blocks of LDs). This conversion is likely protective for the brain and microglia, as we recently showed that long‐chain saturated FFAs can be neurotoxic (Nature 599,102‐107, 2021), but it is not without cost for microglial phagocytic abilities. We demonstrate that a key enzyme for the conversion of FFAs to TAGs, promotes microglial LD formation, is increased in microglia from 5xFAD and human AD brains, and that inhibiting it improved microglial uptake of Aβ.ConclusionThese findings identify a new lipid‐mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.