APOE genotype modifies microglial immunometabolism. (20th December 2022)

• Record Type: Journal Article
• Authors: Devanney, Nicholas A.; Lee, Sangderk; Williams, Holden C.; Allenger, Elizabeth J.; Smith, Cathryn T; Segovia, Gabriella Morillo; Walsh, Adeline E.; Friday, Cassi; Morganti, Josh M.; Johnson, Lance A
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.067248
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Metabolic dysfunction and neuroinflammation characterize Alzheimer's disease (AD), but it is unclear if these two facets of the disease are linked. The E4 allele of Apolipoprotein E ( APOE ) is the strongest genetic risk factor for late‐onset AD and is associated with increased neuroinflammation. Recent data from our lab and others show that E4 is also associated with increased aerobic glycolysis. These two findings may be intrinsically linked through the concept of 'immunometabolism' ‐ an emerging paradigm that implicates increased glycolysis as a core requirement during pro‐inflammatory activation, whereas increased oxidative phosphorylation is required for anti‐inflammatory responses. Method: Primary microglia were isolated from targeted replacement mice expressing human APOE isoforms and stimulated with pro‐inflammatory (lipopolysaccharide (LPS); IFNγ + TNFα) or anti‐inflammatory (IL‐10; IL‐4 + IL‐13) cytokines. Metabolic responses were measured using the Agilent Seahorse platform and targeted metabolomics. We also performed single‐cell RNA sequencing on brains from APOE targeted replacement mice at 3‐, 10‐, and 18 months of age +/‐ LPS. Result: Seahorse revealed increased glycolysis and decreased mitochondrial respiration in E4 microglia. Targeted metabolomics revealed increased lactate and succinate in E4 microglia, metabolites known to accumulate in pro‐inflammatory macrophages. Aged E4 brains were uniquely found to harbor a metabolically distinct subcluster of microglia that expressed a signature similar to the established 'disease associated microglia' phenotype, even in the absence of neuropathology. SCENIC regulon analysis linked this cluster to the transcription network of HIF1a, and increased expression of HIF1a was validated in E4 microglia. In LPS‐treated animals, two distinct microglia subclusters emerged in E4 brains that were defined by altered expression of genes relating to oxidative phosphorylation and mitochondrial function. Conclusion: Our findings reveal that age and LPS treatment induce a distinct metabolic response in E4 microglia. The accumulation of lactate and succinate and increased glycolysis in E4 microglia indicate altered metabolic preference conducive to pro‐inflammatory activation, whereas the decreased mitochondrial respiration may preclude effective anti‐inflammatory responses. We propose that this altered metabolism skews E4 microglia towards a phenotype that favors chronic neuroinflammation and neurodegeneration. Thus, reprogramming metabolism in E4 microglia may provide a novel therapeutic avenue for the treatment of AD.