Details

Autor(en) / Beteiligte

• Lee, Sangderk
• Devanney, Nicholas A.
• Golden, Lesley R.
• Smith, Cathryn T.
• Schwartz, James L.
• Walsh, Adeline E.
• Clarke, Harrison A.
• Goulding, Danielle S.
• Allenger, Elizabeth J.
• Morillo-Segovia, Gabriella
• Friday, Cassi M.
• Gorman, Amy A.
• Hawkinson, Tara R.
• MacLean, Steven M.
• Williams, Holden C.
• Sun, Ramon C.
• Morganti, Josh M.
• Johnson, Lance A.

Titel

APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Ist Teil von

• Cell reports (Cambridge), 2023-03, Vol.42 (3), p.112196-112196, Article 112196

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• The E4 allele of Apolipoprotein E (APOE) is associated with both metabolic dysfunction and a heightened pro-inflammatory response: two findings that may be intrinsically linked through the concept of immunometabolism. Here, we combined bulk, single-cell, and spatial transcriptomics with cell-specific and spatially resolved metabolic analyses in mice expressing human APOE to systematically address the role of APOE across age, neuroinflammation, and AD pathology. RNA sequencing (RNA-seq) highlighted immunometabolic changes across the APOE4 glial transcriptome, specifically in subsets of metabolically distinct microglia enriched in the E4 brain during aging or following an inflammatory challenge. E4 microglia display increased Hif1α expression and a disrupted tricarboxylic acid (TCA) cycle and are inherently pro-glycolytic, while spatial transcriptomics and mass spectrometry imaging highlight an E4-specific response to amyloid that is characterized by widespread alterations in lipid metabolism. Taken together, our findings emphasize a central role for APOE in regulating microglial immunometabolism and provide valuable, interactive resources for discovery and validation research. [Display omitted] •APOE4 and age interact to drive DAM-like signatures in the absence of AD pathology•APOE4 microglia have increased aerobic glycolysis and higher Hif1α expression•APOE4 exacerbates plaque-induced microglial reactivity and lipid metabolism•Mass spectrometry imaging reveals distinct phospholipid distribution in E4FAD brains Lee et al. integrate single-cell and spatially resolved -omics technologies to systematically characterize APOE4’s role in the brain’s response to aging, peripheral inflammatory challenge, and amyloid pathology. E4 microglia display a unique metabolic response to each of these paradigms, with increased aerobic glycolysis and altered expression of lipid metabolism pathways.