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

Abstract

Several microglia-expressed genes have emerged as top risk variants for Alzheimer′s disease (AD). 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. Here we show that microglia form lipid droplets (LDs) upon exposure to amyloid-beta (Aβ), and that their LD load increases with proximity to amyloid plaques in brains from human patients and the AD mouse model 5xFAD. LD formation is dependent upon age and disease progression and is more prominent in the hippocampus in mice and humans. 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 Aβ phagocytosis. Unbiased lipidomic analysis identified a substantial decrease in free fatty acids (FFAs) and a parallel increase in triacylglycerols (TAGs) as the key metabolic transition underlying LD formation. We demonstrate that DGAT2, 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 DGAT2 improved microglial uptake of Aβ. These findings identify a new lipid-mediated mechanism underlying microglial dysfunction that could become a novel therapeutic target for AD.

Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia

“…Excess fatty acids are often stored in triglyceride-rich lipid droplets, which we observed by microscopy (Figure 1G,H). Other studies have observed increased levels of microglial lipid droplets in the contexts of aging, disease, and inflammation 15,23,24,27,32 , suggesting that lipid accumulation in microglia is a central biological phenomenon and operates in multiple contexts. To further understand the functional consequences of lipid accumulation we chose to interrogate whether lipid accumulation was necessary for microglial activation or whether it was an epiphenomenon.…”

Lesion-remote astrocytes govern microglia-mediated white matter repair

“…Lipid extraction from the frozen microglial cell pellets was done following Bligh and Dyer protocol with slight modifications 88,89 . Briefly, the pellets were thawed at 4 °C for 10 mins, after which, cold methanol, and HPLC-grade chloroform were added in a ratio of 2:1.…”

“…A volume of 8μL of diluted lipid extract was introduced into the Agilent Jet Stream (AJS) ion source of the mass spectrometer by flow injection for each MRM method. Briefly, MRM methods were established for 10 lipid classes and spanned 1497 individual lipid species 89,90 . Lipid classes of interest were phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), acyl carnitine (CAR), cholesterol ester (CE), diacylglycerol (DG), triacylglycerol (TG), and sphingomyelin (SM).…”

“…Statistical analysis of MRM transitions in lipids for all sample comparisons were conducted using the edgeR software package 91 based on our previous study 89,90 . The ion count of each lipid was denoted by ‘l’ for a given sample ‘s’.…”

Brain Lipids and Lipid Droplet Dysregulation in Alzheimer’s Disease and Neuropsychiatric Disorders

“…In general, besides the interplay between sex hormones and ApoE risk loci, the drastic metabolic changes occurring during the critical period of perimenopause in women also increase oxidative stress in the brain [191], which may further lead to accumulation of LDs in specific brain cell types and contribute to sex-specific AD vulnerability. For example, female microglia show an increase of several long-chain species of TAGs with more LDs; such LDladen microglia that are chronically exposed to Aβ exhibit a dysfunctional phagocytosis [201].…”