Microglia-Dependent and Independent Modulation of Brain Lipid Metabolism in Alzheimer's Disease Revealed by Pharmacological and Genetic Microglial Depletion

Abnormal lipid metabolism in Alzheimers disease (AD) was first documented by Alois Alzheimer in his early observations of patients with a then unrecognized brain disease, which he noted was characterized by a significant presence of "adipose inclusions" or "lipoid granules". Despite this early recognition, until recently the significance of abnormal lipid metabolism in AD has been largely overlooked by the scientific community for decades, highlighting a critical gap in our understanding of this complex disease. In the past decade, numerous loci and genes with genome-wide significant evidence of affecting AD risk have been reported. Notably, a significant portion of these AD risk genes are either preferentially or exclusively expressed by microglia in the brain and/or code for enzymes that directly or indirectly regulate lipid metabolism. This suggests a major, yet uncharacterized, role of microglia in modulating brain lipid metabolism under AD pathological conditions. In our study, we dissected microglia-dependent and independent regulation of lipid metabolism in an AD-like mouse model of amyloidosis, 5xFAD, taking advantage of pharmacological and genetic interventions to eliminate microglia. Using multidimensional mass spectrometry-based shotgun lipidomics (MDMS-SL), we identified overt changes in a number of AD-associated lipids (ADALs) in postmortem patient brains and mouse models of amyloidosis. This included bis(monoacylglycerol)phosphate (BMP), a lipid class enriched in endosomal/lysosomal compartments, and the two most abundant classes of lysophospholipids: lysophosphatidylcholine (LPC) and lysophosphatidylethanolamine (LPE), which are commonly associated with inflammation. Our findings revealed that microglial depletion prevented the accumulation of arachidonic acid-containing BMP species, which are associated with lysosomal activation induced by amyloidosis via a mechanism that involves progranulin, coded by AD risk gene GRN, as shown by targeted transcriptomics, immunoblotting, and immunofluorescence. Surprisingly, AD-associated LPC and LPE accumulation was not driven by microglia. Instead, LPC accumulation correlated with astrocytic activation, while LPE accumulation seems to be associated with oxidative stress. In summary, we uncovered novel microglia-dependent and independent mechanisms that drive lipid dysregulation in AD. These findings may be mechanistically linked with the early glial lipoid deposits described by Dr. Alzheimer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/624173v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@6fe55aorg.highwire.dtl.DTLVardef@3a7d10org.highwire.dtl.DTLVardef@1e8c247org.highwire.dtl.DTLVardef@2ac75f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract.C_FLOATNO C_FIG