Lipoprotein Lipase Regulates Lipid and Lipoprotein Processing in Microglia

Abstract

AbstractBackgroundLipoprotein Lipase (LPL) is the rate‐limiting enzyme in lipoprotein hydrolysis. In the brain, LPL is predominantly expressed in microglia and is a key feature of phagocytic disease‐associated microglia thought to be protective in AD. Indeed, we have previously shown that microglia lacking LPL show impaired phagocytosis, lipid uptake, and cholesterol efflux (Bruce et al., 2018; Loving et al., 2021). Since ApoE4‐containing brain‐derived lipoproteins increase AD risk, we investigated how LPL regulates microglial lipoprotein processing.MethodHDL‐like lipoproteins were isolated from ApoE2, ApoE3, and ApoE4, expressing astrocytes using HPLC. ApoE‐containing lipoproteins were used as substrates in LPL activity assays and cellular lipoprotein uptake experiments. CRISPR‐Cas9 generated LPL knock‐out (LPL KO) cells were used as genetic controls. To further test the role of LPL in the development of AD we generated a novel microglial‐specific LPL knock‐down mouse (MiLPLKD) on the 5xFAD background (MiLPLKD;5xFAD).ResultApoE4 containing lipoproteins were hydrolyzed less efficiently than ApoE2 and ApoE3 containing lipoproteins by purified LPL in enzymatic activity assays. In addition, ApoE4 containing lipoproteins were endocytosed less efficiently than ApoE2 and ApoE3 containing lipoproteins by LPL expressing microglia. In contrast, LPL‐mediated lipoprotein uptake was inhibited when lipoproteins were pre‐incubated with Aβ. Finally, MiLPLKD;5xFAD mice showed exacerbated cognitive deficits compared to MiLPLKD or 5xFAD controls.ConclusionWhile LPL mediates microglial‐lipoprotein uptake, both lipoprotein hydrolysis and endocytosis is inhibited in the presence of ApoE4. This suggests that LPL‐mediated lipoprotein uptake is a critical homeostatic mechanism in the brain that is dysregulated in the presence of ApoE4, contributing to AD progression.