Cellular Energy Metabolism is Altered in the Trem2R47h NSS Mouse Model of AD
Joseph Bishop, Michael M Vu, Rond Malhas, Amrita K Cheema, Giedre Milinkeviciute, Grant R MacGregor, Kim N Green, Andrea J Tenner, Frank LaFerla, Mark Mapstone, MODEL AD Consortium- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Human GWAS have identified variants of the triggering receptor expressed on myeloid cells 2 (TREM2) gene as a major genetic risk factor for Alzheimer’s disease (AD). TREM2 is necessary for maintaining microglial metabolic fitness and may be critical for providing cellular energy demands for microglial‐dependent β amyloid phagocytosis. Here, we examine the plasma metabolome of Trem2 R47H NSS mice in the presence of β amyloid plaques to examine alterations of cellular energy metabolites.
Method
We examined the abundance of plasma metabolites obtained from homozygous Trem2 R47H NSS (Jax #034036), 5xFAD x Trem2 R47H NSS, 5xFAD hemizygous, and control (WT) mice (n = 10 each group) at 4 months of age. We measured 762 lipids and 204 polar metabolites from peripheral plasma using liquid chromatography mass spectrometry (LC‐MS). We conducted differential abundance (DA) analysis for the individual metabolites and compared the groups using FDR correction (q < 0.05). We used DA metabolites in pathway analysis to examine which metabolic pathways were impacted by TREM2 R47H and the presence of amyloid (5xFAD hemizygous background).
Result
Homozygous Trem2 R47H NSS mice, both in the presence and absence of amyloid plaques (i.e. 5xFAD hemizygous or non‐transgenic background), had significantly lower abundance α‐D‐glucose and lactate compared to their relevant control groups (q’s < 0.05). 5xFAD x Trem2 R47H NSS mice also showed significantly lower phosphatidylethanolamine (PE) abundance relative to 5xFAD hemizygous mice (q’s < 0.05) and this was especially apparent for female mice (q’s < 0.05). KEGG pathway analysis using DA features revealed enrichment on Glycerophospholipid Metabolism and Glycolysis/Gluconeogenesis pathways.
Conclusion
We report lower levels of the entry substrate to glycolysis (Glucose) and an end product metabolite (Lactate) in homozygous Trem2 R47H NSS mice, especially in the presence of amyloid. The depletion of these energy metabolites in circulating blood may reflect failure of the immunometabolic switch from oxidative phosphorylation to glycolysis in support of increased energy demands of activated microglia. We also find significant depletion of glycerophospholipids in Trem2 R47H NSS mice, which was more pronounced for female mice. These results suggest cellular energy dyshomeostasis associated with microglial activation which can be measured in peripheral blood.