A locked immunometabolic switch underlies TREM2 R47H loss of function in human iPSC‐derived microglia

Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveilla...

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Published in:	The FASEB journal Vol. 34; no. 2; pp. 2436 - 2450
Main Authors:	Piers, Thomas M., Cosker, Katharina, Mallach, Anna, Johnson, Gabriel Thomas, Guerreiro, Rita, Hardy, John, Pocock, Jennifer M.
Format:	Journal Article
Language:	English
Published:	United States John Wiley and Sons Inc 01-02-2020
Subjects:	Alzheimer Disease - metabolism Alzheimer Disease - pathology Alzheimer's disease Cell Differentiation - genetics Cell Line glycolysis Humans Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Loss of Function Mutation Membrane Glycoproteins - genetics Membrane Glycoproteins - metabolism metabolism microglia Microglia - metabolism Microglia - pathology Receptors, Immunologic - genetics Receptors, Immunologic - metabolism metabolism Alzheimer's disease microglia glycolysis
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Summary:	Loss‐of‐function genetic variants of triggering receptor expressed on myeloid cells 2 (TREM2) are linked with an enhanced risk of developing dementias. Microglia, the resident immune cell of the brain, express TREM2, and microglial responses are implicated in dementia pathways. In a normal surveillance state, microglia use oxidative phosphorylation for their energy supply, but rely on the ability to undergo a metabolic switch to glycolysis to allow them to perform rapid plastic responses. We investigated the role of TREM2 on the microglial metabolic function in human patient iPSC‐derived microglia expressing loss of function variants in TREM2. We show that these TREM2 variant iPSC‐microglia, including the Alzheimer's disease R47H risk variant, exhibit significant metabolic deficits including a reduced mitochondrial respiratory capacity and an inability to perform a glycolytic immunometabolic switch. We determined that dysregulated PPARγ/p38MAPK signaling underlies the observed phenotypic deficits in TREM2 variants and that activation of these pathways can ameliorate the metabolic deficit in these cells and consequently rescue critical microglial cellular function such as β‐Amyloid phagocytosis. These findings have ramifications for microglial focussed‐treatments in AD.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0892-6638 1530-6860
DOI:	10.1096/fj.201902447R