Isoform- and cell-state-specific lipidation of ApoE in astrocytes

Apolipoprotein E transports lipids and couples metabolism between astrocytes and neurons. The E4 variant (APOE4) affects these functions and represents a genetic predisposition for Alzheimer's disease, but the molecular mechanisms remain elusive. We show that ApoE produces different types of li...

Full description

Saved in:
Bibliographic Details
Published in:Cell reports (Cambridge) 2022-03, Vol.38 (9), p.110435-110435, Article 110435
Main Authors: Lindner, Karina, Beckenbauer, Katharina, van Ek, Larissa C., Titeca, Kevin, de Leeuw, Sherida M., Awwad, Khader, Hanke, Franziska, Korepanova, Alla V., Rybin, Vladimir, van der Kam, Elizabeth Louise, Mohler, Eric G., Tackenberg, Christian, Lakics, Viktor, Gavin, Anne-Claude
Format: Article
Language:English
Subjects:
ABCA1
Alzheimer's disease
Apolipoprotein E4 - genetics
Apolipoprotein E4 - metabolism
Apolipoproteins E - metabolism
Astrocytes - metabolism
iPSC-derived astrocyte
lipid droplet
lipid metabolism
lipid transport
lipid-binding
lipidomics
lipoprotein
Protein Isoforms - metabolism
triacylglycerol
Triglycerides - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Apolipoprotein E transports lipids and couples metabolism between astrocytes and neurons. The E4 variant (APOE4) affects these functions and represents a genetic predisposition for Alzheimer's disease, but the molecular mechanisms remain elusive. We show that ApoE produces different types of lipoproteins via distinct lipidation pathways. ApoE forms high-density lipoprotein (HDL)-like, cholesterol-rich particles via the ATP-binding cassette transporter 1 (ABCA1), a mechanism largely unaffected by ApoE polymorphism. Alternatively, ectopic accumulation of fat in astrocytes, a stress-associated condition, redirects ApoE toward the assembly and secretion of triacylglycerol-rich lipoproteins, a process boosted by the APOE4 variant. We demonstrate in vitro that ApoE can detect triacylglycerol in membranes and spontaneously assemble lipoprotein particles (10–20 nm) rich in unsaturated triacylglycerol, and that APOE4 has remarkable properties behaving as a strong triacylglycerol binder. We propose that fatty APOE4 astrocytes have reduced ability to clear toxic fatty acids from the extracellular milieu, because APOE4 reroutes them back to secretion. [Display omitted] •The N terminus of ApoE binds to PIPs and TAG in an isoform-specific manner•Lean astrocytes secrete cholesterol-loaded ApoE; this is unaffected by polymorphism•Fatty astrocytes chronically exposed to fatty acids produce TAG-rich ApoE particles•APOE4 boosts TAG secretion, whereas APOE2 is less active and behaves as APOE-KO Apolipoprotein E (ApoE) provides the metabolic link between astrocytes and neurons. Lindner et al. show that astrocytes produce different types of ApoE-containing particles, depending on their genotype and metabolic status. APOE4 astrocytes with excess lipid droplets have a reduced ability to clear fatty acids and secrete potentially toxic triacylglycerol-rich particles.
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2022.110435